Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia

ABSTRACT

The present invention relates to deuterated 1-piperazino-3-phenyl-indanes and salts thereof with activity at dopamine receptors D1 and D2 as well as the 5HT2 receptors in the central nervous system, to medicaments comprising such compounds as active ingredients, to the use of such compounds in the treatment of diseases in the central nervous system, and to methods of treatment comprising administration of such compounds.

This application is a continuation of U.S. patent application Ser. No.16/146,625, filed Sep. 28, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/435,826, filed Feb. 17, 2017, and issued as U.S.Pat. No. 10,118,907 on Nov. 6, 2018, which is a continuation of U.S.patent application Ser. No. 14/941,800, filed Nov. 16, 2015, and issuedas U.S. Pat. No. 9,617,231 on Apr. 11, 2017, which is a continuation ofU.S. patent application Ser. No. 14/656,925, filed Mar. 13, 2015, andissued as U.S. Pat. No. 9,216,961 on Dec. 22, 2015, which is acontinuation of U.S. patent application Ser. No. 13/924,849, filed Jun.24, 2013, and issued as U.S. Pat. No. 9,012,453 on Apr. 21, 2015, whichis a continuation of U.S. patent application Ser. No. 13/527,364, filedJun. 19, 2012 and issued as U.S. Pat. No. 8,575,174 on Nov. 5, 2013,which claims priority to U.S. Provisional Application No. 61/498,651,filed on Jun. 20, 2011, and 61/537,103, filed on Sep. 21, 2011, theentirety of each of which is incorporated herein by reference.

All patents, patent applications and publications cited herein arehereby incorporated by reference in their entirety. The disclosures ofthese publications in their entireties are hereby incorporated byreference into this application in order to more fully describe thestate of the art as known to those skilled therein as of the date of theinvention described and claimed herein.

FIELD OF THE INVENTION

The present invention relates to deuterated1-piperazino-3-phenyl-indanes and salts thereof with activity atdopamine D₁ and D₂ receptors as well as the serotonin 5HT₂ receptors inthe central nervous system, to medicaments comprising such compounds asactive ingredients, and to the use of such compounds in the treatment ofdiseases in the central nervous system.

BACKGROUND OF THE INVENTION

Throughout this application, various publications are referenced infull. The disclosures of these publications are hereby incorporated byreference into this application to describe more fully the state of theart to which this invention pertains.

4-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine andsalts thereof, pharmaceutical compositions containing these salts andthe medical use thereof, including treatment of schizophrenia or otherdiseases involving psychotic symptoms, are disclosed in WO2005/016900.4-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine hasthe general formula (X), hereinafter referred to as Compound (X)

EP 638 073 recites a group of trans isomers of3-aryl-1-(1-piperazinyl)indanes substituted in the 2- and/or 3-positionof the piperazine ring. The compounds are described as having highaffinity for dopamine D₁ and D₂ receptors and the 5-HT₂ receptors andare suggested to be useful for treatment of several diseases in thecentral nervous system, including schizophrenia.

The enantiomer of formula (X) above has been described by Bøgesø et al.in J. Med. Chem., 1995, 38, 4380-4392, in the form of the fumarate salt(see table 5) compound (−)-38. This publication concludes that the(−)-enantiomer of compound 38 is a potent D₁/D₂ antagonist showing someD₁ selectivity in vitro. The compound is also described as a potent5-HT₂ antagonist. It is also mentioned that the compound does not inducecatalepsy in rats.

The aetiology of schizophrenia is not known, but the dopamine hypothesisof schizophrenia (Carlsson, Am. J. Psychiatry 1978, 135, 164-173),formulated in the early 1960s, has provided a theoretical framework forunderstanding the biological mechanisms underlying this disorder. In itssimplest form, the dopamine hypothesis states that schizophrenia isassociated with a hyperdopaminergic state, a notion which is supportedby the fact that all antipsychotic drugs on the market today exert somedopamine D₂ receptor antagonism (Seeman, Science and Medicine 1995, 2,28-37). However, whereas it is generally accepted that antagonism ofdopamine D₂ receptors in the limbic regions of the brain plays a keyrole in the treatment of positive symptoms of schizophrenia, theblockade of D₂ receptors in striatal regions of the brain causesextrapyramidal symptoms (EPS). As described in EP 638 073, a profile ofmixed dopamine D₁/D₂ receptor inhibition has been observed with someso-called “atypical” antipsychotic compounds, in particular withclozapine(8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine),used in treatment of schizophrenic patients.

Further, selective D₁ antagonists have been connected to treatment ofsleep disorders and alcohol abuse (D. N. Eder, Current Opinion inInvestigational Drugs, 2002 3(2), 284-288).

Dopamine may also play an important role in the aetiology of affectivedisorders (P. Willner, Brain. Res. Rev. 1983, 6, 211-246; Bøgesø et al,J. Med. Chem., 1985, 28, 1817-1828).

EP 638 073 describes how compounds having affinity for 5-HT₂ receptors,in particular 5-HT_(2A) receptor antagonists, have been suggested fortreatment of different diseases, such as schizophrenia including thenegative symptoms in schizophrenic patients, depression, anxiety, sleepdisturbance, migraine attacks and neuroleptic-induced parkinsonism.5-HT_(2A) receptor antagonism has also been suggested to reduce theincidence of extrapyramidal side effects induced by classicalneuroleptics (Balsara et al., Psychopharmacology 1979, 62, 67-69).

An isotopic substitution of one or more hydrogen atoms (H) by deuteriumatoms (D) in a compound may give rise to a kinetic isotope effect whichmay influence the reaction rate, e.g., metabolism of the compound. Thisis particularly the case when the isotopic replacement is in a chemicalbond that is broken or formed in a rate limiting step. In such a case,the change is termed a primary isotope effect. When the isotopicsubstitution(s) are not involved in one or more bonds that are broken asmaller rate change, termed the secondary isotope effect may beobserved.

SUMMARY OF THE INVENTION

The present invention provides compounds wherein one or more hydrogenatoms atoms (H) in one or more of the metabolic sites M1, M2, and M3 ofCompound (X) have been substituted by deuterium atoms (D).

In one aspect, the invention provides a compound of formula Y:

wherein, R¹-R¹⁰ are independently hydrogen or deuterium, and wherein atleast one of R¹-R¹⁰ comprises at least about 50% deuterium, or apharmaceutically acceptable acid addition salt thereof.

In another aspect, the invention provides pharmaceutical compositionscomprising a compound of formula (Y) and one or more pharmaceuticallyacceptable carriers, diluents, or excipients.

In another aspect, the invention provides for uses of a compound offormula (Y) or a pharmaceutical composition comprising a compound offormula (Y) in the treatment of psychosis, other diseases involvingpsychotic symptoms, psychotic disorders, or diseases that present withpsychotic symptoms.

In yet another aspect, the invention provides for the manufacture of amedicament comprising a compound of formula (Y) for treatment ofpsychosis, other diseases involving psychotic symptoms, psychoticdisorders, or diseases that present with psychotic symptoms.

In still another aspect, the invention provides for methods of treatingpsychosis, other diseases involving psychotic symptoms, psychoticdisorders, or diseases that present with psychotic symptoms comprisingadministration of an effective amount of a compound of formula (Y) or apharmaceutically composition comprising a compound of formula (Y) to asubject in need thereof.

In still another aspect, the invention provides a compound of formula

In still another aspect, the invention provides a process for thepreparation of compound

comprising treating compound (XIV) with [(5)-BINAP]Rh(I)BF₄.

In still another aspect, the invention provides a process for thepreparation of compound (1R,3S)-(IV) tartrate comprising, treatment ofracemic trans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃), 2,2-trimethyl-piperazine with L-(+)-tartaric acid.

Still other objects and advantages of the invention will become apparentto those of skill in the art from the disclosure herein, which is simplyillustrative and not restrictive. Thus, other embodiments will berecognized by the skilled artisan without departing from the spirit andscope of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows major metabolic sites of Compound (X).

FIG. 2 shows Compound (I) and Compound (XI), each as the(1R,3S)-enantiomer.

FIGS. 3A and 3B show NMR spectra of Compound (II) and Compound (V).Selected regions of the proton-decoupled and proton- anddeuterium-decoupled ¹³C NMR spectra of Compound (II) (FIG. 3A) andCompound (V) (FIG. 3B) are shown.

FIG. 4 shows the mass spectrum of Compound (IV).

FIG. 5 shows formation of the metabolite Compound (XI) by metabolism ofCompound (X) and Compound (I) (0.1 microM) in cryopreserved doghepatocytes (n=2; bars represent max and min results).

FIG. 6 shows formation of the metabolite Compound (XI) by metabolism ofCompound (X) and Compound (I) (1 microM) in cryopreserved doghepatocytes (n=2; bars represent max and min results).

FIG. 7 shows formation of the desmethyl metabolite by metabolism ofCompounds (II), (IV), and (X) (1 micro M) in human liver microsomes(n=3; bars represent standard deviation).

FIG. 8 shows formation of the desmethyl metabolite by metabolism ofCompounds (II), (IV), and (X) (10 micro M) in human liver microsomes(n=3; bars represent standard deviation).

FIG. 9 shows formation of the desmethyl metabolite by metabolism ofCompound (III) (10 micro M) in human liver microsomes (n=3; barsrepresent standard deviation).

FIG. 10 shows formation of the desmethyl metabolite by metabolism ofCompound (V) (10 micro M) in human liver microsomes (n=3; bars representstandard deviation).

FIG. 11 shows formation of the desmethyl metabolite by metabolism ofCompound (VI) (10 micro M) in human liver microsomes (n=3; barsrepresent standard deviation).

FIG. 12 shows formation of the desmethyl metabolite by metabolism ofCompound (VII) (10 micro M) in human liver microsomes (n=3; barsrepresent standard deviation).

FIG. 13 shows the chemical structure of compounds (I)-(VII), (X)-(XI),and (XIX)-(XXI).

FIG. 14 shows formation of the desmethyl metabolite by metabolism ofCompound (II) and (X) (10 micro M) by recombinant human liver CYP2C19(n=3; bars represent the standard deviation).

FIG. 15 shows formation of the desmethyl metabolite by metabolism ofCompound (IV) and Compound (X) (1 micro M) by recombinant human liverCYP2C19 (n=3; bars represent standard deviation).

FIG. 16 shows PCP-induced hyperactivity in mice for compound (IV).

FIG. 17 shows cataleptic response in rats for compound (IV).

FIG. 18 shows X-ray diffractograms on two batches of hydrogen tartratesalt of Compound (IV).

DETAILED DESCRIPTION OF THE INVENTION

Atypical antipsychotics have been the subject of numerous studies by thepharmaceutical industry, and have shown promise in treating mentaldisorders such as schizophrenia, bipolar disorder, dementia, anxietydisorder, and obsessive-compulsive disorder (OCD). The mechanism ofaction of these agents remains unknown; however all antipsychotics workto some degree on the dopamine system. Most atypical antipsychoticsexhibit activity at dopamine subtype receptors 1 and 2 (D₁ and D₂,respectively), and at the serotonin receptors subtype 2 (5-HT₂). In somecases, the “atypical” designation was assigned to antipsychotics thatdid not induce extrapyramidal side effects; however it has been shownthat some atypical antipsychotics still induce extrapyramidal sideeffects, albeit to a lesser degree that that observed with typicalantipsychotics (Weiden, P. J., “EPS profiles: The AtypicalAntipsychotics Are Not All the Same,” J. Psychiatr. Pract. 2007, 13(1):13-24; herein incorporated by reference in its entirety). Approvedatypical antipsychotics include, for example, amisulpride (Solian),aripiprazole (Abilify), asenapine (Saphris), blonanserin (Lonasen),clotiapine (Entumine), clozapine (Clozaril), iloperidone (Fanapt),lurasidone (Latuda), mosapramine (Cremin), olanzapine (Zyprexa),paliperidone (Invega), perospirone (Lullan), quetiapine (Seroquel),remoxipride (Roxiam), risperidone (Risperdal), sertindole (Serdolect),supliride (Sulpirid, Eglonyl), ziprasidone (Geodon, Zeldox), andzotepine (Nipolept). Several others are currently under development.Because the mechanism of atypical antipsychotics is not well understood,side effects associated with these drugs have been difficult to designaround. Thus, there is a need for additional antipsychotic therapieswith potential for reduced side effects and/or improved therapeuticprofile relative to existing therapies.

In one aspect, the present invention provides compounds wherein one ormore hydrogen atoms (H) in one or more of the metabolic sites M1, M2,and M3 of Compound (X) have been substituted by deuterium atoms (D).Compound (X) and variants thereof are described in, for example, U.S.Pat. Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; and 8,076,342;U.S. Patent Application Publication Nos. 2008/0269248; 2010/0069676;2011/0178094; and 2011/0207744; WO 2005/016900; EP 0 638 073; and J.Med. Chem. 1995, 38, 4380-4392; each herein incorporated by reference inits entirety.

The kinetic isotope effect may potentially influence the rate ofmetabolism at one or more of the metabolic sites M1, M2, and M3indicated in FIG. 1. The inventors of the present invention haveidentified three major metabolic sites of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine(Compound (X)) denoted herein as M1, M2, and M3 and indicated in FIG. 1.

Deuteration of a compound at a site subject to oxidative metabolism may,in some cases, reduce the rate of metabolism for a compound due to theprimary isotope effect. If the C—H bond cleavage step is rate limiting,a significant isotope effect may be observed. However, if other stepsdrive the rate of metabolism for a compound, the C—H bond cleavage stepis not rate limiting and the isotope effect may be of littlesignificance. Additionally, a negative isotope effect can be observedwhere reaction rate is increased upon substitution with deuterium. Thus,incorporation of deuterium at a site subject to oxidative enzymaticmetabolism does not predictably impact pharmacokinetics (See, forexample, U.S. Pat. No. 7,678,914; Drug Metab. Dispos. 1986, 14, 509;Arch. Toxicol. 1990, 64, 109; and Int. Arch. Occup. Environ. Health1993, 65(Suppl. 1): 5139; each herein incorporated by reference in itsentirety). The impact of deuterium incorporation is unpredictable anddoes not work for many drugs or classes of drugs. Decreased metabolicclearance has been observed with some deuterated compounds relative tonon-deuterated derivatives; whereas metabolism of other compounds hasbeen unimpacted. Examples of studies indicating lack of predictabilityregarding deuterium incorporation include U.S. Pat. No. 6,221,335; J.Pharm. Sci. 1975, 64, 367-391; Adv. Drug. Res. 1985, 14, 1-40; J. Med.Chem. 1991, 34, 2871-2876; Can. J. Physiol. Pharmacol. 1999, 79-88;Silverman, R. B., The Organic Chemistry of Drug Design and Drug Action,2^(nd) Ed. (2004), 422; Curr. Opin. Drug Dev. 2006, 9, 101-109; ChemicalRes. Tox. 2008, 1672; Harbeson, S. L and Tung, R. D., “Deuterium in DrugDiscovery and Development,” in Ann. Rep. Med. Chem. 2011, 46, 404-418;each herein incorporated by reference in its entirety. Evenincorporation of deuterium at known sites of metabolism has anunpredictable impact on metabolic profile. Metabolic switching mayresult wherein the metabolic profile of a particular drug is changed dueto deuterium incorporation, thus leading to different proportions of (ordifferent) metabolites than observed with a non-deuterated analog of thesame drug. The new metabolic profile may result in a distincttoxicological profile of the deuterated analog. Adding to the potentialcomplications of deuterium incorporation is the possibility ofdeuterium/hydrogen exchange in the physiological environment (Adv. Drug.Res. 1985, 14, 1-40; herein incorporated by reference in its entirety).

In some embodiments, isotopic substitution of one or more hydrogen atomsin Compound (X) by deuterium atoms has given rise to a kinetic isotopeeffect that influences the rate of metabolism.

The isotopic substitution of hydrogen atoms in Compound (X) by deuteriumatoms results in less metabolism of the deuterated compound as shown tooccur in dog hepatocytes where, for instance, an approximately 50%decrease in formation of the desmethyl metabolite (Compound (XI)) fromCompound (I) (FIG. 2) was noted in comparison to the formation ofCompound (XI) from the metabolism of Compound (X).

Deuteration of the free phenyl, optionally in combination withdeuteration of the 1-methyl group (Compound (II) and (IV)), surprisinglyreduces the amount of the desmethyl metabolite produced in human livermicrosomes as compared to the non-deuterated compound (Compound (X)).Also, surprisingly, deuteration of the 1-methyl group impactedmetabolism in dog but not human hepatocytes, thus indicative of theunpredictability of deuteration on pharmacological properties.

The effect of the reduced metabolism is higher bioavailability of thedeuterated, parent compound and less metabolite formation. Without beingbound by theory, based on the results described in the experimentalsection of this application the same effect is expected to show up aftermultiple dosing in humans, allowing for lower doses to be administeredto humans, i.e., less burden to the entire body, e.g., the liver, and aless frequent dosing.

The desmethyl metabolite (Compound (XI)) is known to have hERG affinityand thus potentially contribute to QTc prolongation. As mentioned above,deuteration of the free phenyl optionally in combination withdeuteration of the 1-methyl group (Compound (II) and (IV)), surprisinglyreduces the amount of the desmethyl metabolite produced in human livermicrosomes as compared to the non-deuterated compound (Compound (X)).Accordingly, and without being bound by theory, it is anticipated thatthere will be less interaction with the hERG channel and resultant lowerburden on the heart when dosing the deuterated variants of Compound (X)[e.g., compounds of formula (Y)] compared to when dosing Compound (X).

The invention is further detailed in the exemplary embodiments providedherein.

Definitions

The term “compound(s) of the invention” as used herein means Compounds(Y), (I), (II), (III), (IV), (V), (VI), and/or (VII), and may includesalts, hydrates and/or solvates thereof. The compounds of the presentinvention are prepared in different forms, such as salts, hydrates,and/or solvates, and the invention includes compositions and methodsencompassing all variant forms of the compounds.

The term “composition(s) of the invention” as used herein meanscompositions comprising Compounds (Y), (I), (II), (III), (IV), (V),(VI), and/or (VII), or salts, hydrates, and solvates thereof. Thecompositions of the invention may further comprise one or more chemicalcomponents such as, for example, excipients, diluents, vehicles, orcarriers.

The term “method(s) of the invention” as used herein means methodscomprising treatment with the compounds and/or compositions of theinvention.

As used herein the term “about” is used herein to mean approximately,roughly, around, or in the region of. When the term “about” is used inconjunction with a numerical range, it modifies that range by extendingthe boundaries above and below the numerical values set forth. Ingeneral, the term “about” is used herein to modify a numerical valueabove and below the stated value by a variance of 20 percent up or down(higher or lower).

An “effective amount”, “sufficient amount,” or “therapeuticallyeffective amount” as used herein is an amount of a compound that issufficient to effect beneficial or desired results, including clinicalresults. As such, the effective amount may be sufficient, for example,to reduce or ameliorate the severity and/or duration of an affliction orcondition, or one or more symptoms thereof, prevent the advancement ofconditions related to an affliction or condition, prevent therecurrence, development, or onset of one or more symptoms associatedwith an affliction or condition, or enhance or otherwise improve theprophylactic or therapeutic effect(s) of another therapy. An effectiveamount also includes the amount of the compound that avoids orsubstantially attenuates undesirable side effects.

As used herein and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, including clinicalresults. Beneficial or desired clinical results may include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions, diminution of extent of disease, a stabilized (i.e., notworsening) state of disease, preventing spread of disease, delay orslowing of disease progression, amelioration, or palliation of thedisease state and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.

The term “in need thereof” refers to the need for symptomatic orasymptomatic relief from a condition such as, for example, psychosis ora psychotic disorder. The subject in need thereof may or may not beundergoing treatment for conditions related to, for example, psychosisor a psychotic disorder.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehiclewith which a compound is administered. Non-limiting examples of suchpharmaceutical carriers include liquids, such as water and oils,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.The pharmaceutical carriers may also be saline, gum acacia, gelatin,starch paste, talc, keratin, colloidal silica, urea, and the like. Inaddition, auxiliary, stabilizing, thickening, lubricating, and coloringagents may be used. Other examples of suitable pharmaceutical carriersare described in Remington: The Science and Practice of Pharmacy,21^(st) Edition (University of the Sciences in Philadelphia, ed.,Lippincott Williams & Wilkins 2005) (hereby incorporated by reference inits entirety).

The terms “animal”, “subject”, and “patient” as used herein include allmembers of the animal kingdom including, but not limited to, mammals,animals (e.g., cats, dogs, horses, swine, etc.), and humans.

The term “isotopic variant” as used herein means a compound obtained bysubstituting one or more hydrogen in a parent compound not comprisingdeuterium atoms by deuterium atoms.

It is recognized that elements are present in natural isotopicabundances in most synthetic compounds, and result in inherentincorporation of deuterium. However, the natural isotopic abundance ofhydrogen isotopes such as deuterium is immaterial (about 0.015%)relative to the degree of stable isotopic substitution of compoundsindicated herein. Thus, as used herein, designation of an atom asdeuterium at a position indicates that the abundance of deuterium issignificantly greater than the natural abundance of deuterium. Any atomnot designated as a particular isotope is intended to represent anystable isotope of that atom, as will be apparent to the ordinarilyskilled artisan.

Compounds (Y) are isotopic variants of Compound (X).

In some embodiments, compounds (I), (II), (III), (IV), (V), (VI), and(VII) are isotopic variants of Compound (X).

M1 is a site of Compound (X) susceptible to metabolism; M1 consists of—CH₂— in the 6-position of the piperazine of Compound (X).

M2 is a site of compound (X) susceptible to metabolism; M2 consists ofthe N-bound methyl of the piperazine of Compound (X).

M3 is a site of Compound (X) susceptible to metabolism; M3 consists ofthe phenyl group of Compound (X).

Parent compound is the chemical compound which is the basis for itsderivatives obtained either by substitution or breakdown, e.g.,metabolic breakdown. In the context of the present invention, the parentcompound is the active pharmaceutical ingredient (API).

In some embodiments, any atom not designated as deuterium is present atits natural isotopic abundance. In some embodiments, any hydrogen atomnot designated as deuterium is present at less than 1% isotopicabundance of deuterium.

In one aspect, the invention provides a compound of formula (Y):

wherein, R¹-R¹⁰ are independently hydrogen or deuterium, wherein atleast one of R¹-R¹⁰ comprises at least about 50% deuterium, or apharmaceutically acceptable acid addition salt thereof.

In another aspect, the invention provides pharmaceutical compositionscomprising a compound of formula (Y) and one or more pharmaceuticallyacceptable carriers, diluents, or excipients.

In another aspect, the invention provides for uses of a compound offormula (Y) or a pharmaceutical composition comprising a compound offormula (Y) in the treatment of psychosis, other diseases involvingpsychotic symptoms, psychotic disorders, or diseases that present withpsychotic symptoms.

In yet another aspect, the invention provides for the manufacture of amedicament comprising a compound of formula (Y) for treatment ofpsychosis, other diseases involving psychotic symptoms, psychoticdisorders, or diseases that present with psychotic symptoms.

In still another aspect, the invention provides for methods of treatingpsychosis, other diseases involving psychotic symptoms, psychoticdisorders, or diseases that present with psychotic symptoms comprisingadministration of an effective amount of a compound of formula (Y) or apharmaceutically composition comprising a compound of formula (Y).

In some embodiments, the compound is racemic. In some embodiments, thecompound is enantiomerically enriched.

In some embodiments, the compound is selected from the group consistingof

In some embodiments, R¹ and R² comprise deuterium, R³-R⁵ comprisedeuterium, or R⁶-R¹⁰ comprise deuterium.

In some embodiments, R¹ and R² comprise deuterium. In some embodiments,R¹ and R² comprise deuterium and R³-R⁵ comprise hydrogen.

In some embodiments, R³-R⁵ comprise deuterium. In some embodiments,R³-R⁵ comprise hydrogen.

In some embodiments, R⁶-R¹⁰ comprise deuterium. In some embodiments,R⁶-R¹⁰ comprise deuterium and R³-R⁵ comprise hydrogen.

In some embodiments, R¹-R⁵ comprise deuterium.

In some embodiments, R¹, R², and R⁶-R¹⁰ comprise deuterium.

In some embodiments, R³-R¹⁰ comprise deuterium.

In some embodiments, 10-R¹⁰ comprise deuterium.

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, the compound is

In some embodiments, at least about 75% of the compound has a deuteriumatom at each position designated as deuterium, and any atom notdesignated as deuterium is present at about its natural isotopicabundance.

In some embodiments, at least about 85% of the compound has a deuteriumatom at each position designated as deuterium, and any atom notdesignated as deuterium is present at about its natural isotopicabundance.

In some embodiments, at least about 90% of the compound has a deuteriumatom at each position designated as deuterium, and any atom notdesignated as deuterium is present at about its natural isotopicabundance.

In some embodiments, the compound is a salt selected from the groupconsisting of fumarate, maleate, succinate, and tartrate. In someembodiments, the compound is a fumarate salt. In some embodiments, thecompound is a hydrogen fumarate salt. In some embodiments, the compoundis a maleate salt. In some embodiments, the compound is a hydrogenmaleate salt. In some embodiments, the compound is a succinate salt. Insome embodiments, the compound is a hydrogen succinate salt. In someembodiments, the compound is a tartrate salt. In some embodiments, thecompound is the hydrogen tartrate salt.

In some embodiments, the compound is the hydrogen tartrate salt of(1R,3S)-(IV).

In some embodiments, the psychosis or disease involving psychoticsymptoms is schizophrenia, schizophreniform disorder, schizoaffectivedisorder, delusional disorder, brief psychotic disorder, sharedpsychotic disorder, bipolar disorder, or mania in bipolar disorder. Insome embodiments, the psychosis or disease involving psychotic symptomsis schizophrenia.

In some embodiments, the methods further comprise administration withone or more neuroleptic agents.

In some embodiments, the uses further comprise use of a one or moreneuroleptic agents.

In some embodiments, the neuroleptic agent is selected from the groupconsisting of sertindole, olanzapine, risperidone, quetiapine,aripiprazole, haloperidol, clozapine, ziprasidone, and osanetant.

In some embodiments, administration is oral, sublingual, or buccal. Insome embodiments, administration is oral.

In some embodiments, the subject is a mammal. In some embodiments, thesubject is a rodent, cat, dog, monkey, horse, swine, bovine, or human.In some embodiments, the subject is a rodent, cat, dog, monkey, bovine,or human. In some embodiments, the subject is a mouse, rat, cat, dog,monkey, or human. In some embodiments, the subject is a mouse, rat, dog,monkey, or human. In some embodiments, the subject is a mouse, rat, dog,or human. In some embodiments, the subject is a mouse, rat, or a human.In some embodiments, the subject is a dog or a human. In someembodiments, the subject is a human.

In some embodiments, designation of a position as “D” in a compound hasa minimum deuterium incorporation of greater than about 40% at thatposition. In some embodiments, designation of a position as “D” in acompound has a minimum deuterium incorporation of greater than about 50%at that position. In some embodiments, designation of a position as “D”in a compound has a minimum deuterium incorporation of greater thanabout 60% at that position. In some embodiments, designation of aposition as “D” in a compound has a minimum deuterium incorporation ofgreater than about 65% at that position. In some embodiments,designation of a position as “D” in a compound has a minimum deuteriumincorporation of greater than about 70% at that position. In someembodiments, designation of a position as “D” in a compound has aminimum deuterium incorporation of greater than about 75% at thatposition. In some embodiments, designation of a position as “D” in acompound has a minimum deuterium incorporation of greater than about 80%at that position. In some embodiments, designation of a position as “D”in a compound has a minimum deuterium incorporation of greater thanabout 85% at that position. In some embodiments, designation of aposition as “D” in a compound has a minimum deuterium incorporation ofgreater than about 90% at that position. In some embodiments,designation of a position as “D” in a compound has a minimum deuteriumincorporation of greater than about 95% at that position. In someembodiments, designation of a position as “D” in a compound has aminimum deuterium incorporation of greater than about 97% at thatposition. In some embodiments, designation of a position as “D” in acompound has a minimum deuterium incorporation of greater than about 99%at that position.

Pharmaceutically Acceptable Salts

The present invention also comprises salts of the compounds, typically,pharmaceutically acceptable salts. Such salts include pharmaceuticallyacceptable acid addition salts. Acid addition salts include salts ofinorganic acids as well as organic acids.

Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic,nitric acids, and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic,lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic,picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic,tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids,theophylline acetic acids, as well as the 8-halotheophyllines, forexample 8-bromotheophylline, and the like. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in Berge, S. M. etal., J. Pharm. Sci. 1977, 66, 2, and Gould, P. L., Int. J. Pharmaceutics1986, 33, 201-217; the contents of each are hereby incorporated byreference.

Furthermore, the compounds of this invention may exist in unsolvated aswell as in solvated forms with pharmaceutically acceptable solvents suchas water, ethanol, and the like. In general, the solvated forms areconsidered comparable to the unsolvated forms for the purposes of thisinvention.

Headings and sub-headings are used herein for convenience only andshould not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (including “forinstance”, “for example”, “e.g.”, and “as such”) in the presentspecification is intended merely to better illuminate the invention, anddoes not pose a limitation on the scope of invention unless otherwiseindicated.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context.

Unless otherwise indicated, all exact values provided herein arerepresentative of corresponding approximate values (e.g., all exactexemplary values provided with respect to a particular factor ormeasurement can be considered to also provide a correspondingapproximate measurement, modified by “about,” where appropriate).

The description herein of any aspect or aspect of the invention usingterms such as “comprising”, “having,” “including,” or “containing” withreference to an element or elements is intended to provide support for asimilar aspect or aspect of the invention that “consists of”, “consistsessentially of”, or “substantially comprises” that particular element orelements, unless otherwise stated or clearly contradicted by context.

Exemplary syntheses of the compounds of the invention can be readilyachieved by methods described, for example, U.S. Pat. Nos. 5,807,855;7,648,991; 7,767,683; 7,772,240; and 8,076,342; U.S. Patent ApplicationPublication Nos. 2008/0269248; 2010/0069676; 2011/0178094; and2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38,4380-4392; each herein incorporated by reference in its entirety. Suchmethods, and similar methods can be performed using deuterated reagentsand/or intermediates, and/or introducing deuterium atoms to a chemicalstructure according to protocols known in the art.

Further exemplary methods of synthesis include conversion of indanone Ato intermediate C via treatment of 3-bromo-6-chloro-indan-1-one (A; forreferences on this material, see: Bøgesø EP 35363 A1 19810909 andKehler, Juhl, Püschl, WO 2008025361; each herein incorporated byreference in its entirety) with a base such as triethylamine in asolvent such as tetrahydrofuran at ambient temperature (Scheme 1).Removal of the precipitated amine hydrobromide salt by filtration andconcentration of the filtrate will afford 6-chloro-inden-1-one (B). Thismaterial can be reacted with phenyl-d₅-boronic acid in the presence ofapproximately 1 equivalent of a base such as triethylamine and acatalytic amount of a 1:1 mixture of [Rh(ndb)₂]BF₄(bis(norbornadiene)rhodium(I) tetrafluoroborate) and racemic BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) in a suitable solvent(e.g., approximately 10:1 solvent mixture of 1,4-dioxane and water)under an atmosphere of argon at elevated temperature (e.g., about 100°C.). Work-up will afford racemic 6-chloro-3-phenyl-d₅-indan-1-one (C).

Treatment of 6-chloro-3-phenyl-d₅-indan-1-one (C) with a reductive basesuch as sodium borohydride (˜2 equivalents) in a ˜10:1 solvent mixtureof tetrahydrofuran and water at low temperature (approximately −15° C.)will lead to reduction of the carbonyl group to the correspondingalcohol (Scheme 2). Work-up will afford racemiccis-6-chloro-3-phenyl-indan-1-ol (D). Treatment of this material withvinyl butyrate (approximately 5 equivalents) and Novozym 435° in asolvent such as di-iso-propyl ether at ambient temperature will afford(1S,3S)-6-chloro-3-phenyl-indan-1-ol (E) after work-up.

Alternatively, performing the sequence from A to E using phenyl boronicacid or 4,4,5,5-tetramethyl-2-phenyl-[1,3,2]dioxaborolane instead of4,4,5,5-tetramethyl-2-d₅-phenyl-[1,3,2]dioxaborolane will lead to(1S,3S)-6-chloro-3-phenyl-indan-1-ol (E′) (Scheme 3).

Further alternative synthetic methods to obtain E′ are disclosed in thepatent literature (Dahl, Wøhlk Nielsen, Suteu, Robin, BrøsenWO2006/086984 A1; Bang-Andersen, Bøgesø, Jensen, Svane, Dahl, Howells,Lyngsø, Mow WO2005/016901 A1; each herein incorporated by reference inits entirety). These procedures rely on benzyl cyanide as one of thesubstrates. Using benzyl cyanide-d₇ (commercially available fromAldrich, catalog #495840) or phenyl-d₅-acetonitrile (commerciallyavailable from Aldrich catalog #495859 or from CDN catalog #D-5340 orfrom Kanto catalog #49132-27) the same procedure may lead to E (Scheme4). As alternatives to the commercial sources, benzyl cyanide-d₇ andphenyl-d₅-acetonitrile can be prepared from sodium cyanide and benzyl-d₇chloride (commercially available from Aldrich, catalog #217336) andbenzyl-2,3,4,5,6-d₅ chloride (commercially available from Aldrich,catalog #485764), respectively.

Treatment of E with approximately 4 equivalents ofdi-iso-propylethylamine and approximately 2 equivalents methanesulphonicanhydride in tetrahydrofuran at approximately −18° C. followed by slowheating to approximately −5° C. and subsequent treatment withapproximately 4 equivalents of 2,2-dimethyl-piperazine will lead to theformation of1-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-3,3-dimethyl-piperazine (F)that can be purified after the reaction (Scheme 5). Alternatively, onecan convert alcohol E to the corresponding chloride, predominantly withretention of configuration at C1 leading to(1S,3S)-1-chloro-3-d₅-phenyl-indan (E″; similarly E′ can be converted to(1S,3S)-1-chloro-3-phenyl-indan (E′″)). Chloride E″ can be reacted with2,2-dimethyl-piperazine to afford F. The final step can be performed asdescribed for the preparation of Compound (I).butanedioic acid salt bythe use of iodomethane to give Compound (II) or d₃-iodomethane to giveCompound (IV), respectively. Alternatively, as described below, themethyl group or d₃-methyl group can be installed by refluxing inHCHO/HCOOH or DCDO/DCOOD, respectively.

(2-Amino-2-methyl-propyl)-carbamic acid tert-butyl ester (G) can beprepared from 2-methyl-propane-1,2-diamine and di-tert-butyl dicarbonate(alternatively, G is claimed to be commercially available: Prime catalog#POI-1362-MB4; Rovathin catalog #NX45401). Reaction of G with ahaloacetyl halide such as either chloroacetyl chloride or bromoacetylbromide will give [2-(2-chloro-acetylamino)-2-methyl-propyl]-carbamicacid tert-butyl ester or[2-(2-bromo-acetylamino)-2-methyl-propyl]-carbamic acid tert-butyl ester(H), respectively (Scheme 6). Treatment of either variant of H with acidfollowed by base will lead to the formation of6,6-dimethyl-piperazine-2-one (I). This material can be reduced to2,2-dimethyl-5,5-d₂-piperazine (J) by treatment with lithium aluminiumdeuteride.

Alternatively, J can be prepared from 2-amino-2-methyl-propionic acid.Reaction of 2-amino-2-methyl-propionic acid and di-tert-butyldicarbonate will afford 2-tert-butoxy carbonylamino-2-methyl-propionicacid (K) (Scheme 7). The acid functionality can be converted to thecorresponding Weinreb amide by reaction with O,N-dimethyl-hydroxylaminein the presence of a suitable coupling reagent such as2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium (HATU) or1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) to afford[1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butylester (L). Selective reduction of the Weinreb amide leads to(1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (M). Reductiveamination involving aldehyde M and amino-acetic acid methyl ester can beused to prepare 2-tert-butoxycarbonylamino-2-methyl-propylamino)-aceticacid methyl ester (N). Treatment of carbamate-ester N with a suitableacid, such as trifluoroacetic acid, will lead to the formation ofpiperazinone I that upon treatment with lithium aluminium deuteridegives piperazine J.

Using J instead of 2,2-dimethyl-piperazine as described for theconversion of E to Compounds (II) and (IV) will lead to Compounds (VI)and Compound (VII), respectively. Similarly, using E′ and J instead of2,2-dimethyl-piperazine and E will lead to Compound (III) and Compound(V).

In another aspect, the invention provides a process for the preparationof compound

comprising treating compound (XIV) with [(5)-BINAP]Rh(I)BF₄.

In another aspect, the invention provides a process of the preparationof compound (1R,3S)-(IV) tartrate comprising treatment of racemictrans-1-(6-chloro-3-phenyl (d₃)-indan-1-yl)-1(d₃), 2,2-trimethyl-piperazine with L-(+)-tartaric acid.

In some embodiments, racemictrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃),2,2-trimethyl-piperazine is generated from the corresponding succinatesalt thereof.

In some embodiments, racemictrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃),2,2-trimethyl-piperazine succinate is generated from the maleate salt ofracemictrans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-3,3-dimethyl-piperazine.

In some embodiments, acetophenone-d₅ is converted to an enol ether. Insome embodiments, the enol ether is a silyl enol ether. In someembodiments, the enol ether of acetophenone-d₅ is converted to thecorresponding vinyl boronate. In some embodiments, the enol ether ofacetophenone-d₅ is treated with bis(pinacolato)diboron. In someembodiments, the vinyl boronate is treated with2-halo-5-chlorobenzaldehyde.

In some embodiments, the compounds exist as racemates. In someembodiments, the compounds exist in greater than about 70% enantiomericexcess. In some embodiments, the compounds exist in greater than about75% enantiomeric excess. In some embodiments, the compounds exist ingreater than about 80% enantiomeric excess. In some embodiments, thecompounds exist in greater than about 85% enantiomeric excess. In someembodiments, the compounds exist in greater than about 90% enantiomericexcess. In some embodiments, the compounds exist in greater than about92% enantiomeric excess. In some embodiments, the compounds exist ingreater than about 95% enantiomeric excess. In some embodiments, thecompounds exist in greater than about 97% enantiomeric excess. In someembodiments, the compounds exist in greater than about 99% enantiomericexcess.

Pharmaceutical Compositions

The present invention further provides pharmaceutical compositionscomprising a therapeutically effective amount of the compounds of thepresent invention and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers, diluents orexcipients, in either single or multiple doses. The pharmaceuticalcompositions according to the invention may be formulated withpharmaceutically acceptable carriers or diluents as well as any otherknown adjuvants and excipients in accordance with conventionaltechniques such as those disclosed in Remington: The Science andPractice of Pharmacy, 21′ Edition (University of the Sciences inPhiladelphia, ed., Lippincott Williams & Wilkins 2005). Furtherexemplary compositions of the compounds of the invention are describedin, for example, U.S. Pat. Nos. 5,807,855; 7,648,991; 7,767,683;7,772,240; and 8,076,342; U.S. Patent Application Publication Nos.2008/0269248; 2010/0069676; 2011/0178094; and 2011/0207744; WO2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392; eachherein incorporated by reference in its entirety.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as oral, nasal, topical(including buccal and sublingual), and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous, and intradermal)routes. It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated, and the active ingredient.

The daily dose of the compounds of the invention, calculated as the freebase, is suitably from about 1.0 to about 160 mg/day, more suitably fromabout 1 to about 100 mg, e.g., preferably from about 2 to about 55, suchas from about 2 to about 15 mg, e.g., from about 3 to about 10 mg. Insome embodiments, the daily dose is from about 0.1 mg to about 500 mg.In some embodiments, the daily dose is from about 1 mg to about 500 mg.In some embodiments, the daily dose is from about 1 mg to about 400 mg.In some embodiments, the daily dose is from about 1 mg to about 300 mg.In some embodiments, the daily dose is from about 1 mg to about 200 mg.In some embodiments, the daily dose is from about 1 mg to about 160 mg.In some embodiments, the daily dose is from about 1 mg to about 100 mg.In some embodiments, the daily dose is from about 1 mg to about 60 mg.In some embodiments, the daily dose is from about 2 mg to about 30 mg.In some embodiments, the daily dose is from about 2 mg to about 15 mg.In some embodiments, the daily dose is from about 3 mg to about 10 mg.In some embodiments, the daily dose is about 60 mg. In some embodiments,the daily dose is about 50 mg. In some embodiments, the daily dose isabout 40 mg. In some embodiments, the daily dose is about 30 mg. In someembodiments, the daily dose is about 20 mg. In some embodiments, thedaily dose is about 10 mg. In some embodiments, the daily dose is about5 mg. In some embodiments, the daily dose is about 3 mg. In someembodiments, the daily dose is about 2 mg. In some embodiments, thedaily dose is about 1 mg.

For parenteral routes such as intravenous, intrathecal, intramuscular,and similar administration, typical doses are in the order of half thedose employed for oral administration.

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. Examples ofsuitable organic and inorganic acids are described herein.

In some embodiments, the composition comprises a cyclodextrin. In someembodiments, the composition comprises a cyclodextrin in water. In someembodiments, the cyclodextrin is hydroxypropyl-β-cyclodextrin. In someembodiments, the composition comprises hydroxypropyl-β-cyclodextrin inwater.

Treatment of Disorders

The invention also relates to the medical use of compounds of thepresent invention, such as for the treatment of a disease in the centralnervous system, including psychosis, in particular schizophrenia orother diseases involving psychotic symptoms, such as, e.g.,schizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, as well other psychotic disorders or diseases that presentwith psychotic symptoms, e.g., bipolar disorder, such as mania inbipolar disorder. Compounds and/or compositions of the invention canfurther be used in treatment of disorders such as those described in,for example, U.S. Pat. Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240;and 8,076,342; U.S. Patent Application Publication Nos. 2008/0269248;2010/0069676; 2011/0178094; and 2011/0207744; WO 2005/016900; EP 0 638073; and J. Med. Chem. 1995, 38, 4380-4392; each herein incorporated byreference in its entirety. The invention also relates to the medical useof compounds of the present invention as combination therapy inconjunction with other therapeutic agents such as those described in,for example, U.S. Pat. Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240;and 8,076,342; U.S. Patent Application Publication Nos. 2008/0269248;2010/0069676; 2011/0178094; and 2011/0207744; WO 2005/016900; EP 0 638073; and J. Med. Chem. 1995, 38, 4380-4392; each herein incorporated byreference in its entirety.

It will be recognized that one or more features of any embodimentsdisclosed herein may be combined and/or rearranged within the scope ofthe invention to produce further embodiments that are also within thescope of the invention.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be within the scope of the present invention.

The invention is further described by the following non-limitingExamples.

EXAMPLES

Examples are provided below to facilitate a more complete understandingof the invention. The following examples illustrate the exemplary modesof making and practicing the invention. However, the scope of theinvention is not limited to specific embodiments disclosed in theseExamples, which are for purposes of illustration only, since alternativemethods can be utilized to obtain similar results.

Purification of compounds by chromatography refers to the application ofsilica gel chromatography using either manual flash chromatography orautomated flash chromatography, typically performed using eluentgradients from heptanes to ethyl acetate or mixtures of ethyl acetate,triethylamine, and methanol.

Description of LCMS Methods.

Compounds (I), (II), (III), (IV), (V), (VI) and (VII) were characterizedby LCMS using the following methods (Table 1):

TABLE 1 Methods for LCMS Analysis. Methods WXV-AB5, WXV-AB10, andWXV-AB30 Equipment Agilent 1100 LCMS system with ELS Detector [methodWuXiAB25 Agilent 1200 LCMS system with ELS Detector] Pump G1311ADegasser G1379A Well-plate Autosampler G1367A Column Oven G1316A DADG1315B MSD G1946C or G1956A [method WuXiAB25 6110] ELSD Alltech ELSD 800[method WuXiAB25 Aligent1200] Column YMC ODS-AQ [method WuXiAB25 AgilentTC-C18] Particle size 5 micrometer Pore size 12 nm Dimension 50 * 2.0 mmID [method WuXiAB25 50 * 2.1 mm ID] Injection volume   2 microL Columntemperature 50° C. Flow 0.8 mL/min Mobile phases A  0.1% TFA in water B0.05% TFA in acetonitrile Total run time  4.5 min Gradient linear UVDetection Wavelength  254 nm ELSD Detection Temperature: 50° C. GasPressure:  3.2 bar Time Gradient WXV-AB05   0 min  95% A 5% B  3.5 min 0% A 100% B 3.55 min  95% A 6% B WXV-AB10   0 min  90% A 10% B  3.4 min100% B  3.5 min 100% B 3.51 min  90% A 10% B WXV-AB30   0 min  70% A 30%B  3.2 min  0% A 100% B  3.5 min  0% A 100%B 3.55 min  70% A 30% BWuXiAB25   0 min  75% A 25% B  3.4 min  0% A 100% B   4 min  0% A 100% B4.01 min  75% A 25% B  4.5 min  75% A 25% B Method 131 Equipment SciexAPI150EX equipped with APPI-source operating in positive ion mode LC-MSwere run on a Sciex API150EX equipped with APPI-source operating inposi-tive ion mode. The HPLC consisted of Shimadzu LC10-ADvp LC pumps,SPD-M20A PDA detector (operating at 254 nM) and SCL-10A systemcontroller. Autosampler was Gilson Autosampler Gilson 215 Column OvenJones Chromatography 7990R ELSD Sedere Sedex 85 Column Waters SymmetryC-18 Particle size 3.5 micrometer Dimension 30 * 4.6 mm ID Injectionvolume  10 microL Column temperature 60° C. Flow 3.0 mL/min Mobilephases A 0.05% TFA in water B 0.05% TFA in methanol Total run time  2.8min Gradient non-linear UV Detection Wavelength  254 nm ELSD DetectionTemperature: 50° C. Gas Pressure:  4.4 bar Time Gradient 0.01 min  17% Bin A 0.27 min  28% B in A 0.53 min  39% B in A 0.80 min  50% B in A 1.07min  59% B in A 1.34 min  68% B in A 1.60 min  78% B in A 1.87 min  86%B in A 2.14 min  93% B in A 2.38 min 100% B 2.40 min  17% B in A 2.80min  17% B in ADescription of Chiral HPLC Methods

The enantiomeric purity was assayed on a Hewlett Packard 1100 seriessystem equipped with a diode array detector and using ChemStation for LCRev. A.08.03[847]. The HPLC method parameters are described in the tablebelow (Table 2). Compound (X) has a retention time around 13.6-13.7 minwhile its enantiomer,4-((1S,3R)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine,elutes at 8.5-8.6 min.

TABLE 2 Methods for Chiral HPLC Analysis Sample Preparation 1-3 mg/mL inhexane/2-propanol (80/20 v/v) Column: Chiralpak ADH 5 microm 250 × 4.6mm Column Temperature (° C.): 30 Injection (microL): 5 Detection: 240, 8Wavelength, Bandwidth (nm): Total run-time 30 min Flow Rate (mL ·min⁻¹): 0.6 Mobile Phase hexane/2-propanol/diethylamine/ propionic acid90/10/0.2/2

Example 1: Preparation of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine.butanedioicacid (Compound (I).Butanedioic Acid Salt)

1-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazinehydrochloride (11.1 g) was dissolved in a mixture of toluene (74 mL) andwater (74 mL). Preparation of1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazinehydrochloride is disclosed in the patent literature (Dahl, WøhlkNielsen, Suteu, Robin, Brøsen WO2006/086984 A1; Bang-Andersen, Bøgesø,Jensen, Svane, Dahl, Howells, Lyngsø, Mow WO2005/016901 A1; each hereinincorporated by reference in its entirety). 12.0 M of potassiumhydroxide in water (5.38 mL), tetra-N-butylammonium bromide (1.42 g),and d₃-iodomethane (Aldrich catalog #176036; 2.4 mL) were added and themixture was stirred at room temperature for 18 hours (Scheme 8). Themixture was filtered through a glass filter into a separatory funnel.The solid on the filter was washed with toluene (50 mL) into theseparatory funnel. The aqueous layer was extracted with toluene (100 mL)and the combined organic layers were washed with concentrated aqueousammonia (100 mL) and subsequently with water (100 mL) before it wasdried over sodium sulfate, filtered, and concentrated in vacuumaffording a slightly yellow oil. The oil was cooled to −78° C. undervacuum which solidified the oil. Upon warming to room temperature, theoil became a semi-solid.

This material was dissolved in acetone (30 mL); in a separate flaskbutanedioic acid (3.46 g) was suspended in acetone (30 mL) and warmed toreflux (not all of the diacid went into solution). The acid suspensionwas added to the solution of the crude product and additional acetone(50 mL) was added to the butanedioic acid residue and then poured intosolution. The mixture was stirred overnight. Partial precipitation hadoccurred overnight, and the mixture was concentrated in vacuum. Theresidue was re-dissolved in acetone (70 mL) and warmed to reflux andallowed to cool to room temperature and stirred for 2 hours.

The mixture was filtered affording4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine.butanedioicacid (Compound (I).butanedioic acid salt; 7.61 g). LC-MS (method 131):RT(UV) 1.57 min; UV/ELS purity 100%/100%; mass observed 358.0.Incorporation of three deuterium atoms >99%. The proton-decoupled ¹³CNMR spectrum showed a heptet around 36.4 ppm corresponding to thedeuterated M2 metabolic site; this signal collapsed to a singlet in theproton- and deuterium-decoupled ¹³C NMR spectrum. All other signals weresinglets in both spectra. Optical purity >95% ee.

Example 2: Alternative method of preparation of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine.butanedioicacid (Compound (I).Butanedioic Acid Salt)

The free base of1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazine wasprepared from the corresponding hydrochloride salt by partitioning 23.4g of the salt between a mixture of water (100 mL), concentrated aqueouspotassium hydroxide (40 mL), and toluene (250 mL). The organic layer waswashed with a mixture of water (50 mL) and concentrated aqueouspotassium hydroxide (10 mL). The combined aqueous layers were extractedwith toluene (75 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuum affording the free base of1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazine (21.0g) as a colorless oil. This material was dissolved in a mixture oftoluene (150 mL) and water (150 mL), before 12.0 M aqueous potassiumhydroxide (11.3 mL), tetra-N-butylammonium bromide (2.98 g), andd₃-iodomethane (4.9 mL) were added, and the mixture was stirred at roomtemperature for 18 hours.

Work-up and purification was performed as described above and afforded4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine.butanedioicacid (Compound (I).butanedioic acid salt; 14.34 g; 48.9%).

Example 3: Preparation of4-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-1,2,2-trimethyl-piperazine(Compound (II)) and4-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine(Compound (IV))

To a solution of compound A (57 g) in tetrahydrofuran (600 mL) was addedtriethylamine (30 mL) dropwise over 30 min. The reaction mixture waskept at room temperature for 3 hours. The precipitated solid wasfiltered and the filtrate was concentrated in vacuo. The residue wasreprecipitated from diethyl ether to afford compound B (31 g) as ayellow solid. To a solution of compound phenyl-d₅-boronic acid (25 g) in1,4-dioxane/water (900 mL/90 mL) was added [Rh(ndb)₂]BF₄ (1.3 g),racemic BINAP (2.1 g), and triethylamine (14 mL), then the reactionmixture was kept at room temperature for 2 hours under N₂. Then,compound indenone (19 g) was added, and the resulting mixture was heatedto 100° C. for 3 hours. The precipitated solid was filtered off. Thefiltrate was concentrated in vacuo. The residue was purified bychromatography to afford indanone C (10 g).

13.4 kg 3-Bromo-6-chloro-indan-1-one (A; for references on thismaterial, see: Bøgesø EP 35363 A1 19810909 and Kehler, Juhl, Püschl, WO2008025361; each herein incorporated by reference in its entirety) wasdissolved in tetrahydrofuran (170.8 L), and the solution was cooled to0-5° C. (Scheme 9). Triethylamine (9.1 L) was added over 0.5 hour. Themixture was stirred at 0-5° C. for 5 hours before an additional portionof triethylamine (2.48 L) was added over 0.5 hour, and stirring wascontinued for 2 hours. The mixture was filtered, and the filtrate wasconcentrated to 30 L before n-heptane (102 L) was added. The volume wasreduced to 60 L. More n-heptane (203 L) was added, and the mixture wasstirred for 1 hour. Silica gel (17.2 kg) was added. The mixture wasfiltered, and the residual solid was washed with n-heptane (100 L). Thecombined filtrates were concentrated to 30 L and stirred at 0-5° C. for1 hour. The mixture was centrifuged, and the residual solid was dried toafford 6-chloro-inden-1-one (compound B; 2.42 kg), sufficiently pure forthe next step.

2-Methyl-tetrahydrofuran (85 L) and NN-dimethyl acetamide (12.4 L) wereadded to a reactor followed by potassium acetate (10.9 kg) andbis(pinacolato)diboron (14.8 kg). The resulting mixture was stirred for0.5 hour. Pd(dppf)Cl₂-DCM (0.91 kg) was added followed bybromobenzene-d₅ (9.0 kg) and 2-methyl-tetrahydrofuran (12.2 L). Themixture was heated to 80-85° C. for 3 hours, before the temperature wasreduced to ambient temperature. The crude mixture was filtered viakieselguhr and silica gel. The filter-cake was washed with2-methyl-tetrahydrofuran (31 L). The combined filtrates wereconcentrated to approximately 25 L while maintaining the temperaturebelow 35° C. n-Heptane (52 L) and 7% aqueous NaHCO₃ (31 L) were added,and the mixture was stirred for 0.5 hour. The organic layer was stirredwith 7% aqueous NaHCO₃ (31 L) for 0.5 hour. The combined aqueous layerswere extracted with n-heptane (22 L) over 0.5 hour. The combined organicextracts were washed with 25% aqueous NaCl (50 L) over 0.5 hour. Theorganic layer was concentrated while maintaining the temperature below35° C. to afford 4,4,5,5-tetramethyl-2-d₅-phenyl-[1,3,2]dioxaborolane(compound B′; 10.5 kg), sufficiently pure for the next step.

To a reactor was added sequentially 1,4-dioxane (85 L),6-chloro-inden-1-one (compound B; 9.09 kg prepared in a similar mannerto the one described above), 1,5-cyclooctadiene (0.2 L),bis(norbornadiene)rhodium(I) tetrafluoroborate (0.52 kg), triethylamine(5.5 L), 4,4,5,5-tetramethyl-2-d₅-phenyl-[1,3,2]dioxaborolane (compoundB′; 6.5 kg), and 1,4-dioxane (26 L). The mixture was heated to 48-53° C.and stirred at that temperature for 5 hours. The reaction was quenchedby the addition of 2M aqueous HCl (13 kg). Then, n-heptane (110 L),methyl tert-butyl ether (32 L), and water (90 L) were added, and theresulting mixture was stirred for 0.3 hour. The organic layer was washedwith water (90 L) over 0.3 hour. The combined aqueous layers wereextracted with a mixture of methyl tert-butyl ether (30 L) and n-heptane(57 L) over 0.3 hour. The combined organic layers were filtered throughsilica gel (13 kg). The filter-cake was washed with a 2:1 mixture ofn-heptane and methyl tert-butyl ether (19.5 kg). The filtrate wasconcentrated to approximately 25 L. n-Heptane (45 L) was added, and thevolume was reduced to approximately 25 L. n-Heptane (45 L) was added,and the volume was reduced to approximately 35 L. The mixture wasstirred at 0-5° C. for 3 hours. The mixture was centrifuged, and theresidual solid was dried to afford racemic6-chloro-3-d₅-phenyl-indan-1-one (compound C; 8.4 kg), sufficiently purefor the next step.

Tetrahydrofuran (90 L) was added to a reactor followed by water (10 L)and 6-chloro-3-d₅-phenyl-indan-1-one (compound C; 7.73 kg) (Scheme 10).The mixture was cooled to −35 to −30° C. Sodium borohydride (1.5 kg) wasadded portion-wise while maintaining the temperature at −35 to −30° C.The resulting mixture was stirred at −35 to −30° C. for 5 hours beforeit was allowed to warm to ambient temperature. Excess sodium borohydridewas quenched by the addition of 2 M aqueous HCl (7.6 kg) whilemaintaining the temperature below 45° C. Water (17 L) and methyltert-butyl ether (67 L) were added and the mixture was stirred for 0.3hour. The aqueous layer was extracted with methyl tert-butyl ether (39L) over 0.3 hour. The combined organic layers were washed with brine (36kg) over 0.3 hour. The organic layer was filtered through silica gel(6.4 kg). The filter-cake was washed with methyl tert-butyl ether (20L). The combined filtrates were concentrated to approximately 30 L whilemaintaining the temperature below 45° C. n-Heptane (55 L) was added andthe resulting mixture was concentrated to approximately 30 L whilemaintaining the temperature below 45° C. The resulting mixture wasstirred at 0-5° C. for 2 hours. The mixture was centrifuged, and thefilter-cake was washed with n-heptane (12 L) before it was centrifugedagain. The residual solid was dried to afford crude D. 4.87 kg of thismaterial was dissolved in methyl tert-butyl ether (20 L) and dried overNa₂SO₄ (2 kg) over 0.25 hour. The mixture was filtered, and thefilter-cake was washed with methyl tert-butyl ether (4.4 L). Thecombined filtrate was concentrated to approximately 20 L whilemaintaining the temperature below 45° C. n-Heptane (32 L) was added andthe mixture was to approximately 25 L while maintaining the temperaturebelow 45° C. n-Heptane (16 L) was added and the mixture was toapproximately 20 L while maintaining the temperature below 45° C. Thesolid was filtered off and dried to afford racemiccis-6-chloro-3-d₅-phenyl-indan-1-ol (compound D; 4.99 kg), sufficientlypure for the next step.

To a solution of racemic cis-6-chloro-3-d₅-phenyl-indan-1-ol (compoundD; 50 g) in 2-isopropoxypropane (200 mL) was added vinyl butyrate (120mL) and Novozym-435 (15 g). The mixture was kept at ambient temperaturefor 2 days. The solid was filtered off. The filtrate was evaporated andpurified by chromatography on silica gel to afford(1S,3S)-6-chloro-3-d₅-phenyl-indan-1-ol (compound E; 13 g), sufficientlypure for the next step.

Aa solution of (1S,3S)-6-chloro-3-d₅-phenyl-indan-1-ol (compound E; 7 g)in THF (100 mL) was treated with SOCl₂ (6.6 g) at ambient temperatureovernight. The mixture was poured into ice-cold water and extracted withethyl acetate. The organic layer was washed with brine. The organiclayer was dried over Na₂SO₄, filtered, and concentrated in vacuo toafford the intermediate chloride (7.5 g). 3.5 g of this material wasdissolved in 2-butanone (50 mL) and reacted with 2,2-dimethyl-piperazine(1.7 g) in the presence of K₂CO₃ (2.7 g) at reflux overnight. The solidwas filtered off. The filtrate was concentrated in vacuo and the residuewas purified by preparative HPLC on a Shimadzu FRC-10A instrument fittedwith a Synergi C18 column (250 mm*50 mm, 10 μm) using water andacetonitrile (containing 0.1% TFA, v/v) as the eluent to afford1-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-3,3-dimethyl-piperazine(compound F; 2.6 g), sufficiently pure for the next step.

A solution of1-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-3,3-dimethyl-piperazine(compound F; 2.2 g) in HCHO/HCOOH (3 mL/3 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenethyl acetate and 10% aqueous NaOH. The organic layer was dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine(Compound (II); 1.89 g). LC-MS (method WXV-AB05): RT(UV) 2.43 min;UV/ELS purity 95.1%/99.6%; mass observed 360.2. Incorporation of fivedeuterium atoms >95%. The proton-decoupled ¹³C NMR spectrum showed threetriplets around 126.1, 127.2, and 128.2 ppm corresponding to thedeuterated M3 metabolic sites; these signals collapsed to three singletsin the proton- and deuterium-decoupled ¹³C NMR spectrum. All othersignals were singlets in both spectra. Optical purity >95% ee.

A solution of1-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-3,3-dimethyl-piperazine(compound F; 3.0 g) in DCDO/DCOOD (4 mL/4 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenethyl acetate and 10% aqueous NaOH. The organic layer was dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1-d₃-methyl-2,2-diimethyl-piperazine(Compound (IV); 2.14 g). LC-MS (method WXV-AB10): RT(UV) 2.06 min;UV/ELS purity 98%/100%; mass observed 363.3. Incorporation of eightdeuterium atoms >94%. The proton-decoupled ¹³C NMR spectrum showed aheptet around 36.4 ppm corresponding to the deuterated M2 metabolicsite; this signal collapsed to a singlet in the proton- anddeuterium-decoupled ¹³C NMR spectrum. The proton-decoupled ¹³C NMRspectrum further showed three triplets around 126.1, 127.2, and 128.2ppm corresponding to the deuterated M3 metabolic sites; these signalscollapsed to three singlets in the proton- and deuterium-decoupled ¹³CNMR spectrum. All other signals were singlets in both spectra. Opticalpurity >95% ee.

Example 4: Preparation of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine-6,6-d₂(Compound (III)),4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine-6,6-d₂(Compound (V)),4-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine-6,6-d₂(Compound (VI)), and4-((1R,3S)-6-chloro-3-phenyl-d₅-indan-1-yl)-1,2,2-trimethyl-piperazine-6,6-d₂(Compound (VII)

2-Amino-2-methyl-propionic acid (50.0 g) was suspended in a mixture ofmethanol and triethylamine (9:1, 1.2 L) (Scheme 11). 1 M aqueous NaOH(450 mL) was added with stirring until all solid was dissolved.Di-tert-butyl dicarbonate (Boc₂O; 214.0 g) was added, and the mixturewas stirred at ambient temperature overnight. The organic volatiles wereremoved in vacuo. EtOAc (500 mL) was added. The organic layer was washedwith brine and dried over Na₂SO₄, filtered, then concentrated to afford2-tert-butoxycarbonylamino-2-methyl-propionic acid (compound K; 90 g) asa white solid which was used directly in next step.

A mixture of 2-tert-butoxycarbonylamino-2-methyl-propionic acid(compound K; 60.0 g) and 1-ethyl-3(3-dimethylaminopropyl) carbodiimidehydrochloride (EDC.HCl; 86.4 g) in dichloromethane (900 mL) was stirredat ambient temperature, then N,O-dimethyl hydroxylamine hydrochloride(35.3 g) and triethylamine (150 mL) were added. The resulting mixturewas stirred at ambient temperature for 3 days. Water was added and mostof volatiles were removed in vacuo. The residue was partitioned betweenDCM and aqueous NaHCO₃. The organic layer was washed with 3 M aqueousHCl, subsequently with brine before it was dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silica gelchromatography to give[1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butylester (compound L; 28.2 g) as a white solid sufficiently pure for thenext step.

Lithium aluminum hydride (7.8 g) was added to a stirred solution of[1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butylester (compound L; 42.0 g) in dry diethyl ether (1.5 L) at −40° C. Theresulting mixture was stirred at that temperature for about 5 minutes.Excess LiAlH₄ was quenched with a solution of potassium hydrogen sulfatein water. The resulting mixture was partitioned between EtOAc and 3 Maqueous HCl. The organic layer was washed with saturated aqueous NaHCO₃,dried over Na₂SO₄, filtered, and concentrated in vacuo to afford(1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (compound M;29 g), sufficiently pure for the next step.

Amino-acetic acid methyl ester hydrochloride (80.6 g) and Et₃N (160 mL)were dissolved in DCM (1000 mL) and stirred for 15 minutes to liberatethe amine from the salt. Then, a solution of1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (compound M;29.0 g) in DCM (600 mL) was added. The resulting mixture was stirred for0.5 hour at ambient temperature, before NaBH(OAc)₃ (102 g) was added,and then the mixture was stirred at ambient temperature overnight.Saturated aqueous NaHCO₃ was added. The aqueous layer was extracted withDCM. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography to afford (2-tert-butoxycarbonylamino-2-methyl-propylamino)-acetic acid methyl ester (compoundN; 26.5 g) as white solid, which was used directly in the next step.

A mixture of (2-tert-butoxycarbonylamino-2-methyl-propylamino)-aceticacid methyl ester (compound N; 26.5 g) in DCM (800 mL) was stirred atambient temperature, and TFA (180 mL) was added drop-wise. The mixturewas stirred at 30-40° C. for 5 hours before it was concentrated invacuo. The residue was partitioned between dissolved toluene and water.The organic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. The residual solid was dissolved in a mixture of ethanol (400 mL)and methanol (90 mL). K₂CO₃ (207 g) was added and the mixture wasrefluxed overnight. The mixture was cooled to room temperature. DCM (2.5L) was added, and the mixture was stirred for 1 hour at ambienttemperature. The solid was filtered off, and the filtrate wasconcentrated in vacuo to afford 6,6-dimethyl-piperazin-2-one (CompoundI; 5.85 g) as a white solid, sufficiently pure for the next step.

A solution of 6,6-dimethyl-piperazin-2-one (Compound I; 3.6 g) in THF(20 mL) was stirred at 0° C. Lithium aluminum deuteride (LiAlD₄; 3.6 g)was added, then the mixture was refluxed overnight. The mixture wascooled to ambient temperature and Na₂SO₄ was added. The mixture wasstirred for 0.5 hours before most of the volatiles were removed invacuo. The residue was suspended in a saturated solution of HCl in EtOAcat ambient temperature for 0.5 hour. The solid was filtered off anddried to afford to give 2,2-d₂-6,6-dimethyl-piperazine as thebis-hydrochloride salt (Compound J.2HCl; 5.3 g), sufficiently pure forthe next step.

To a solution of compound E′ (5 g) in THF (50 mL) was added SOCl₂ (4.7g), and the resulting mixture was stirred overnight at ambienttemperature (Scheme 12). The mixture was poured into ice-water andextracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo to afford thecorresponding chloride (5.3 g) which was used directly in the next step.3.3 g of this material was dissolved in 2-butanone (50 mL) and reactedwith 2,2-d₂-6,6-dimethyl-piperazine (Compound J; 3 g) in the presence ofK₂CO₃ (8.28 g) at reflux overnight. The solid was filtered off. Thefiltrate was concentrated in vacuo. The residue was purified bypreparative HPLC on a Shimadzu FRC-10A instrument fitted with a SynergyC18 column (250 mm*50 mm, 10 μm) using water and acetonitrile(containing 0.1% TFA, v/v) as the eluents to afford1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound O; 1.7 g).

A solution of1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound O; 0.5 g) in HCHO/HCOOH (1 mL/1 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenEtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine-6,6-d₂(Compound (III); 0.33 g). LC-MS (method WXV-AB30): RT(UV) 1.42 min;UV/ELS purity 100%/100%; mass observed 357.2. Incorporation of twodeuterium atoms >97%. The proton-decoupled ¹³C NMR spectrum showed aquintet around 49.5 ppm corresponding to the deuterated M1 metabolicsite; this signal collapsed to a singlet in the proton- anddeuterium-decoupled ¹³C NMR spectrum. The proton-decoupled ¹³C NMRspectrum further showed three triplets around 126.1, 127.2, and 128.2ppm corresponding to the deuterated M3 metabolic sites; these signalscollapsed to three singlets in the proton- and deuterium-decoupled ¹³CNMR spectrum. All other signals were singlets in both spectra. Opticalpurity >95% ee.

A solution of1-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound O; 0.7 g) in DCDO/DCOOD (1 mL/1 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenEtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine-6,6-d₂(Compound (V); 0.49 g). LC-MS (method WXVAB25): RT(UV) 2.13 min; UV/ELSpurity 100%/100%; mass observed 360.2. Incorporation of five deuteriumatoms >95%. The proton-decoupled ¹³C NMR spectrum showed a heptet around36.4 ppm corresponding to the deuterated M2 metabolic site; this signalcollapsed to a singlet in the proton- and deuterium-decoupled ¹³C NMRspectrum. The proton-decoupled ¹³C NMR spectrum further showed a quintetaround 49.5 ppm corresponding to the deuterated M1 metabolic site; thissignal collapsed to a singlet in the proton- and deuterium-decoupled ¹³CNMR spectrum. All other signals were singlets in both spectra. Opticalpurity >95% ee.

To a solution of (1S,3S)-6-chloro-3-d₅-phenyl-indan-1-ol (compound E; 7g) in THF (100 mL) was treated with SOCl₂ (6.6 g) at ambient temperatureovernight (Scheme 13). The mixture was poured into ice-cold water andextracted with ethyl acetate. The organic layer was washed with brine.The organic layer was dried over Na₂SO₄, filtered, and concentrated invacuo to afford the intermediate chloride (7.5 g).

1.8 g of the intermediate chloride material was dissolved in 2-butanone(30 mL) and reacted with 2,2-d₂-6,6-dimethyl-piperazine (Compound J; 1.4g) in the presence of K₂CO₃ (5.5 g) at reflux overnight. The solid wasfiltered off. The filtrate was concentrated in vacuo. The residue waspurified by preparative HPLC on a Shimadzu FRC-10A instrument fittedwith a Synergy C18 column (250 mm*50 mm, 10 μm) using water andacetonitrile (containing 0.1% TFA, v/v) as the eluents to afford1-((1R,3S)-6-Chloro-3-d₅-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound P; 1.7 g).

A solution of1-((1R,3S)-6-Chloro-3-d₅-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound P; 1 g) in DCDO/DCOOD (1.5 mL/1.5 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenEtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1-d₃-methyl-2,2-dimethyl-piperazine-6,6-d₂(Compound (VI); 0.55 g). LC-MS (method WuXiAB25): RT(UV) 2.13 min;UV/ELS purity 98.2%/100%; mass observed 365.2. Incorporation of tendeuterium atoms >91%. The proton-decoupled ¹³C NMR spectrum showed aheptet around 36.4 ppm corresponding to the deuterated M2 metabolicsite; this signal collapsed to a singlet in the proton- anddeuterium-decoupled ¹³C NMR spectrum. The proton-decoupled ¹³C NMRspectrum further showed a quintet around 49.5 ppm corresponding to thedeuterated M1 metabolic site; this signal collapsed to a singlet in theproton- and deuterium-decoupled ¹³C NMR spectrum. The proton-decoupled¹³C NMR spectrum further showed three triplets around 126.1, 127.2, and128.2 ppm corresponding to the deuterated M3 metabolic sites; thesesignals collapsed to three singlets in the proton- anddeuterium-decoupled ¹³C NMR spectrum. All other signals were singlets inboth spectra. Optical purity >95% ee.

A solution of1-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-3,3-d₂-5,5-dimethyl-piperazine(Compound P; 0.7 g) in HCHO/HCOOH (1 mL/1 mL) was refluxed overnight.The volatiles were removed in vacuo. The residue was partitioned betweenEtOAc and 10% aqueous NaOH. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford4-((1R,3S)-6-chloro-3-d₅-phenyl-indan-1-yl)-1-methyl-2,2-dimethyl-piperazine-6,6-d₂(Compound (VII); 0.47 g). LC-MS (method WXV-AB30): RT(UV) 1.33 min;UV/ELS purity 97.4%/100%; mass observed 362.3. Incorporation of sevendeuterium atoms >93%. The proton-decoupled ¹³C NMR spectrum showed aquintet around 49.5 ppm corresponding to the deuterated M1 metabolicsite; this signal collapsed to a singlet in the proton- anddeuterium-decoupled ¹³C NMR spectrum. The proton-decoupled ¹³C NMRspectrum further showed three triplets around 126.1, 127.2, and 128.2ppm corresponding to the deuterated M3 metabolic sites; these signalscollapsed to three singlets in the proton- and deuterium-decoupled ¹³CNMR spectrum. All other signals were singlets in both spectra. Opticalpurity >95% ee.

Example 5: Description of NMR Determination of the Position(s) BearingDeuterium Rather than Hydrogen

NMR spectra were recorded on a Bruker 600-Avance-III spectrometerequipped with a 5 mm TCI cryoprobe operating at 150.91 MHz for ¹³C. Thesolvent CDCl₃ was used as internal reference for the proton-decoupledexperiments, while the proton- and inverse gated deuterium-decoupledspectra were recorded using gated lock. Difference(s) between the twospectra for the compounds of the invention determine(s) the position(s)of the deuterium atoms. When combining this information summarized inthe table below (Table 3) with the electrospray mass spectrometry datathat determined degree of deuteration, the structures of the compoundsof the invention can be assigned unambiguously.

TABLE 3 Carbon NMR data for compounds. M3 (phenyl group M2 M1 @ ~126.1ppm, (methyl group (methylene group ~127.2 (2C), and @ ~36.4 ppm) @~49.5 ppm) ~128.2 (2C)) ¹³C ¹³C NMR ¹³C ¹³C NMR ¹³C ¹³C NMR NMR proton-NMR proton- NMR proton- proton- and proton- and proton- and de-deuterium- de- deuterium- de- deuterium- Cmpd. coupled decoupled coupleddecoupled coupled decoupled (I) heptet singlet singlet singlet singletssinglets (II) singlet singlet singlet singlet 3 3 triplets singlets(III) singlet singlet quintet singlet 3 3 singlets singlets (IV) heptetsinglet singlet singlet 3 3 triplets singlets (V) heptet singlet quintetsinglet 3 3 singlets singlets (VI) heptet singlet quintet singlet 3 3triplets singlets (VII) singlet singlet quintet singlet 3 3 tripletssinglets Only NMR signals that ‘change’ as a consequence of the presenceof D rather than H in the compounds of the invention are included in thetable.

Relevant regions of the ¹³C proton-decoupled (lower spectrum) and ¹³Cproton- and deuterium-decoupled (upper spectrum) NMR spectra of Compound(II) and Compound (V) are shown in FIG. 3 as representative examples.Selected regions of the proton-decoupled and proton- anddeuterium-decoupled ¹³C NMR spectra of Compound (II) [FIG. 3A] andCompound (V) [FIG. 3B].

Example 6: Description of the Electrospray Mass Spectrometry toDetermine Degree of Deuteration

Instrumentation: Mass spectra of acidic, aqueous solutions of thecompounds were obtained on a Hewlett Packard quadrupole massspectrometer model 1100 LC-MSD. Liquid chromatography was performed onan Agilent 1100 HPLC-system coupled to the mass spectrometer.

Experimental: Solutions of the samples were made by dissolvingapproximately 2 mg substance in 2 mL methanol+18 mL 10 mM ammoniumformate pH 3.0. Subsequently the solutions were diluted 100-fold priorto analysis. In order to get a “clean” peak, the samples werechromatographed using a Waters X-bridge C18, 3.5 microm (150×2.1 mm)column, and 0.1% trifluoroacetic acid/acetonitrile 50/50 as mobilephase. This procedure gave one peak of the compound of interest elutingat ca. 3.6 min, containing both the deuterated compounds of theinvension as well as small quantities of deuterium-deficient species.The mass spectra obtained from these peaks were used to evaluate thespeciation of the target molecules. The results were analyzed in percentof the total amount of substance, adding up to 100%. The actual potencyof the compounds was not analyzed, merely the relative content of thedeuterium deficient species.

As a representative example, the mass spectrum of Compound (IV) is shownin FIG. 4. The isotopic pattern of the protonated Compound (V) [M+H]⁺with mass 363.1 u (362.1 u+1.0 u) and the isotope ions 363.1 u, 364.1 u,365.1 u and 366.1 u was in the ratio 100:25.3:34.9:7.9; calculation forC₂₀H₂₂N₂ClD₈ gives the ratio 100:25.2:34.9:8.3. Furthermore, D₇-analogsand the D₃-analogs were observed at masses 362.1 u and 358.1 u,respectively. The signals at 364 u, 365 u, and 366 u are primarily dueto protonated molecules containing ¹³C and/or ³⁷Cl isotopes instead of¹²C and ³⁵Cl (due to the natural distribution). This data shows that theincorporation of eight deuterium atoms was greater than 94%.

Example 7: Experimental Binding Assays

Description of Human D₂ Binding Assay

The assay was performed as a SPA-based competition-binding in a 50 mMTris pH 7.4 assay buffer containing 120 mM NaCl, 5 mM KCl, 4 mM MgCl₂,1.5 mM CaCl₂), and 1 mM EDTA.

1.5 nM ³H-raclopride (Perkin Elmer, NET 975) was mixed with testcompound before addition of 20 μg of a homogenised human D₂ receptormembrane-preparation and 0.25 mg SPA beads (WGA RPNQ 0001, Amersham) ina total volume of 90 μL. The assay plates were under agitation incubatedfor 60 minutes at room temperature and subsequently counted in ascintillation counter (TriLux, Wallac). The total binding, whichcomprised approximately 15% of added radioligand, was defined usingassay buffer, whereas the non-specific binding was defined in thepresence of 10 μM haloperidol. The non-specific binding constitutedapproximately 10% of the total binding.

Data points were expressed in percent of the specific binding of³H-raclopride and the IC₅₀ values (concentration causing 50% inhibitionof ³H-raclopride specific binding) were determined by non-linearregression analysis using a sigmoidal variable slope curve fitting. Thedissociation constant (K_(i)) was calculated from the Cheng Prusoffequation (K_(i)=IC₅₀/(1+(L/K_(D))), where the concentration of freeradioligand L is approximated to the concentration of added³H-raclopride in the assay. The K_(D) of ³H-raclopride was determined to1.5 nM from two independent saturation assays each performed withtriplicate determinations.

Description of Human D₁ Binding Assay

The assay was performed as a SPA-based competition-binding in a 50 mMTris pH 7.4 assay buffer containing 120 mM NaCl, 5 mM KCl, 4 mM MgCl₂,1.5 mM CaCl₂), and 1 mM EDTA. Approximately 1 nM ³H-SCH23390 (PerkinElmer, NET 930) was mixed with test compound before addition of 2.5 μgof a homogenized human D₁ receptor membrane preparation and 0.25 mg SPAbeads (WGA RPNQ 0001, Amersham) in a total volume of 60 μL.

The assay plates were under agitation incubated for 60 minutes at roomtemperature before the plates were centrifuged and subsequently countedin a scintillation counter (TriLux, Wallac). The total binding, whichcomprised approximately 15% of added radioligand, was defined usingassay buffer, whereas the non-specific binding was defined in thepresence of 10 haloperidol.

Data points were expressed in percent of the specific binding and theIC₅₀ values (concentration causing 50% inhibition of specific binding)and were determined by non-linear regression analysis using a sigmoidalvariable slope curve fitting. The dissociation constant (K_(i)) wascalculated from the Cheng Prusoff equation (K_(i)=IC₅₀/(1±(L/K_(D))),where the concentration of free radioligand L is approximated to theconcentration of added radio-ligand in the assay.

Description of Human 5-HT2_(A) Binding

The experiment was carried out at Cerep Contract Laboratories (Cat. ref.#471).

Compound (I) was also tested in an in vivo set up demonstrating centraleffects of the compound. By in vivo binding, the compound's in vivoaffinity for D₂ receptors was assessed and occupancy of 60% of thetarget was observed. Occupancy of D₂ receptors is closely linked toantipsychotic effects in animal models and in patients.

Description of In Vivo Binding to D₂ Receptors in Rat Brain

In vivo binding was carried out according to Andersen et al., Eur. J.Pharmacol. 1987, 144, 1-6; herein incorporated by reference in itsentirety) with a few modifications (Kapur S. et al., J. Pharm. Exp.Ther., 2003, 305, 625-631; herein incorporated by reference in itsentirety). Briefly, 6 rats (male Wistar, 180-200 g) were treated with 20mg/kg test compound subcutaneous 30 minutes before receiving 9.4 microCi [³H]-raclopride intravenously via the tail vein.

15 minutes after the injection of the radio ligand, the animals werekilled by cervical dislocation, the brain quickly removed, and striatumand cerebellum dissected out and homogenized in 5 mL (cerebellum in 20mL) ice-cold buffer (50 mM K₃PO₄, pH 7.4). 1.0 mL of the homogenate wasfiltered through 0.1% PEI-soaked Whatman GF/C filters. This wascompleted within 60 seconds subsequent to the decapitation. Filters werewashed 2 times with 5 mL ice-cold buffer and counted in a scintillationcounter. A group of vehicle-treated animals was used to determine[³H]-raclopride total binding in striatum and non-specific binding incerebellum. The homogenate was measured for protein content by the BCAprotein determination assay (Smith P. K. et al., Anal. Biochem., 1985,150, 6-85; herein incorporated by reference in its entirety).

Example 8: Investigation of the metabolism of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine(Compound (X)) and4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine(Compound (I))

Cryopreserved dog (male Beagle dog) hepatocytes (1 million cells/mL insuspension, 50 μL/well) were pre-incubated for 15 minutes in a 96-wellplate at 37° C. water bath in DMEM high glucose buffered with 1 M HEPES.The cell suspension was added with 50 μL test compounds (finalconcentration 0.1 or 1 μM of4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine(Compound (X)) or4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine(Compound (I)) and further incubated for 0, 15, 45, 75, and 120 minutes.The reaction was stopped by addition of 100 μL acetonitrile to the cellsuspension, and the samples were then removed for LC-MS analysis of thedesmethyl metabolite (Compound (XI)). Data were expressed as MS arearelative to an internal standard.

The results (FIGS. 5 and 6) show that the amount of the desmethylmetabolite (Compound (XI)) produced in cryopreserved dog hepatocytes islower from the deuterated form (Compound (I)) than from the parentcompound (Compound (X)), both at a concentration of 0.1 μM (FIG. 5) andat a concentration of 1 μM (FIG. 6).

Example 9: Pharmacological Testing of Compounds4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-d₃-methyl-2,2-dimethyl-piperazine(Compound (I))

4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-d₃-methyl-2,2-dimethyl-piperazine(Compound (I)) was tested in three in vitro assays for dopamine D₁,dopamine D₂ and serotonin 5-HT_(2A) affinity.

The experiments were carried out as described in the section titled“Binding assays”. The experimental results showed the followingaffinities for4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1-methyl-d₃-2,2-dimethyl-piperazine:D₁: K_(i) log mean=7.5 nM (pK_(i) 0.88±0.15); D₂: K_(i) log mean=34 nM(pK_(i) 1.54±0.11); and 5HT_(2A): IC₅₀=1.14 nM

These binding affinities indicate that Compound (I) has biologicalactivity likely to exert antipsychotic effect.

Pharmacological Testing of Compound (II) and Compound (IV):

The experiments were carried out as described in the section titled“Binding assays”. The experimental results for the two compounds areprovided below.

Compounds (II) and Compound (IV) were tested in two in vitro assays fordopamine D₁ and dopamine D₂ affinity.

Compound (IV): D₁: K_(i) log mean=26.1 nM (pK_(i) 1.42±0.03). D₂: K_(i)log mean=26.7 nM (pK_(i) 1.43±0.04)

Compound (II): D₁: K_(i) log mean=23.2 nM (pK_(i) 1.37±0.03). D₂: K_(i)log mean=26.5 nM (pK_(i) 1.42±0.03)

These binding affinities indicate that Compound (II) and (IV) havebiological activity likely to exert antipsychotic effect.

Compounds (II) and (IV) were also tested in an in vivo set updemonstrating central effects of the compound. By in vivo binding, thecompound's in vivo affinity for D₂ receptors was assessed and occupancyof 70% (Compound (IV)) and 75% (Compound (II)) of the target wasobserved. Occupancy of D₂ receptors is closely linked to antipsychoticeffects in animal models and in patients.

Compounds (I)-(VII) and (X) were assayed in a side-by-side analysis atCerep Contract Laboratories (Cat. Refs. #44, 46, and 471). Results ofreceptor binding is listed in Table 4.

TABLE 4 Binding of Compounds to D1, D2 and 5-HT2a. alternative human D₁alternative human D₂ human Cmpd. receptor binding (K_(i)) receptorbinding (K_(i)) 5-HT_(2A) (IC₅₀) (I) 0.10 nM 7.6 nM 0.37 nM; 1.14 nM*(II) 0.20 nM 6.8 nM  1.1 nM (III) 0.36 nM 7.6 nM  1.1 nM (IV) 0.05 nM 10 nM 0.25 nM (V) 0.10 nM 4.8 nM 0.61 nM (VI) 0.10 nM 3.7 nM 0.24 nM(VII) 0.14 nM 5.2 nM 0.33 nM (X) 0.22 nM   7 nM 0.79 nM *Compound (I)was tested twice in this assay.

Example 10: Metabolism Investigations in Pooled Human Liver Microsomes(HLM)

Pooled human liver microsomes (50 donors, from Xenotech) were incubatedwith 1 μM or 10 μM of compound at 37° C. The incubation mixturecontained 50 mM Tris-HCl, 154 mM KCl, 5 mM MgCl₂, and a NADPHregenerating system (1 mM NADP⁺, 5 mM isocitric acid, 1 unit/mLisocitric dehydrogenase, from Sigma-Aldrich). The protein concentrationwas 0.2 mg/mL and the final volume was 0.5 mL. Following a 10-minutepre-incubation, the reaction was initiated by adding Compound. After 0,15, 30, 60, 90, 120, and 180 minutes, the reactions were terminated bytransferring the subcellular fraction to 0.5 mL of stopping reagentcontaining internal standard. The incubations were carried out intriplicate. The samples were centrifuged at 4000 g (4° C., 15 min) andthe supernatants were analyzed by HPLC-MS/MS. Data were expressed as MSarea relative to an internal standard.

The results are shown as the mean of triplicate determinations ±SD.FIGS. 7 and 8 show that the amount of the desmethyl metabolite producedin human liver microsomes is lower from the deuterated form (Compound(II) and Compound (IV)) than from the non-deuterated compound (Compound(X)), both at a concentration of 1 μM (FIG. 7) and at a concentration of10 μM (FIG. 8). Results for Compound (III) are shown in FIG. 9. Resultsfor Compounds (V)-(VII) are shown in FIGS. 10-12, respectively. Thedesmethyl metabolites of compounds (II), (IV) and (X) are compounds (XX)and (XI), respectively (see FIG. 13).

Investigations Using Recombinant Human Liver CYP2C19 and CYP3A4

Recombinant human liver CYP2C19 or CYP3A4 isoenzymes (from BDbiosciences) were incubated with 1 μM or 10 μM Compound (X), Compound(II), or Compound (IV) at 37° C. The incubation mixture contained 50 mMTris-HCl, 154 mM KCl, 5 mM MgCl₂, and a NADPH regenerating system (1 mMNADP⁺, 5 mM isocitric acid, 1 unit/mL isocitric dehydrogenase, fromSigma-Aldrich). The protein concentration was 0.5 mg/mL and the finalvolume was 0.5 mL. Following a 10-minute pre-incubation, the reactionwas initiated by adding Compound (X), Compound (II), and/or Compound(IV). After 0, 15, 30, 60, 90, 120, and 180 minutes, the reactions wereterminated by transferring the subcellular fraction to 0.5 mL ofstopping reagent containing internal standard. The incubations werecarried out in triplicate. The samples were centrifuged at 4000×g (4°C., 15 minutes) and the supernatants were analyzed by HPLC-MS/MS. Datawere expressed as MS area relative to an internal standard.

The results (FIGS. 14 and 15) show that the amount of the desmethylmetabolite produced following incubation with recombinant human liverCYP2C19 enzymes is lower from the deuterated forms (Compound (II) andCompound (IV)) than from the non-deuterated compound (Compound (X)),both at a concentration of 10 μM (FIG. 14, Compound (II)) and at aconcentration of 1 μM (FIG. 15, Compound (IV)). Corresponding resultswere obtained for Compound (II) at a concentration of 1 μM and forCompound (IV) at a concentration of 10 μM.

Correspondingly, the amount of the desmethyl metabolite produced byincubation with recombinant human liver CYP3A4 enzymes is lower from thedeuterated forms (Compound (II) and (IV)) than from the non-deuteratedcompound (Compound (X)), both at a concentration of 1 mM and 10 mM.

Example 11: Pharmacology of Compound (IV)

PCP-Induced Hyperactivity

Compound (IV) dose-dependently reverses PCP-induced hyperactivity inmice, indicative of antipsychotic efficacy (FIG. 16). Compound (IV)hydrogen tartrate was administered subcutaneous (s.c.) 30 minutes beforethe test. PCP hydrochloride (2.3 mg/kg) was administered s.c. justbefore the test. Locomotor activity was measured for 60 minutes asnumber of beam breaks (counts). Eight-to-16 male mice were used in eachgroup. ## indicates P<0.01 versus Vehicle-PCP (One-way analysis ofvariance [ANOVA] followed by Bonferroni post-hoc test). PCP is blockingNMDA receptors and as such is used to model the hypo-glutamatergic staterelated to schizophrenia. PCP produces behavioral effects in animalsreminiscent of positive, negative, and cognitive symptoms ofschizophrenia patients (Jentsch, J. D. and Roth, R. H.,Neuropsychopharmacology 1999, 20, 201-225; herein incorporated byreference in its entirety). PCP-induced hyperactivity is commonly usedas an assay for evaluation of antipsychotic compounds (Jackson, D. M. etal., Pharmacol. Biochem. Behay. 1994, 48, 465-471; herein incorporatedby reference in its entirety).

Catalepsy

Catalepsy is thought to reflect drug-induced suppression of the abilityto initiate a behavioral response. The catalepsy test in rats is acommon and widely used preclinical screening test for the EPS liabilityof potentially antipsychotic drugs. Although catalepsy is usuallyassessed following acute drug administration, the test has proven to bea reliable predictor for the propensity of an antipsychotic drug toinduce EPS (that is, pseudo parkinsonism, dystonia) in humans (Elliott,P. J. et al, J. Neural. Transm. Park. Dis. Dement. Sect. 1990, 2, 79-89;herein incorporated by reference in its entirety).

Compound (IV) dose-dependently induced catalepsy in rats suggestive ofEPS liability. The minimal effective dose inducing catalepsy was 10mg/kg (FIG. 17). Compound (IV) tartrate was administered s.c. 30 minutesbefore the test. Eight male Sprague Dawley rats were used in each group.# indicates P<0.05, ## indicates P<0.01 versus vehicle (One-way ANOVAfollowed by Bonferroni post-hoc test). This dose is 100 times higherthan the dose indicating antipsychotic activity (FIG. 16).

Example 12: Human Pharmacokinetic Studies

The pharmacokinetics of Compound (IV) and Compound (X) were compared ina multiple oral dose study in healthy young men. The study participantsreceived daily doses of 3 mg Compound (IV) and 3 mg Compound (X) for 18days and blood samples were collected for 24 hours (one dosing interval)after the last dose to measure the exposure of both compounds and theirdemethylated metabolites, Compound (XX) and Compound (XI), respectively.

For all study participants, the area under the time-plasma concentrationcurve for the dosing interval (AUC 0-24) for Compound (IV) was higherthan that for Compound (X), mean 104 h*ng/mL vs 98 h*ng/mL. A consistentshift in the opposite direction was observed for the demethylatedmetabolites with mean AUC 0-24 of 117 h*ng/mL and 120 h*ng/ml forCompound (XX) and Compound (XI), respectively.

Example 13: Catalytic Enantioselective Synthesis of Ketone Intermediate

This example discloses the synthesis of(S)-6-chloro-3-phenyl(d₅)-indan-1-one, Compound (XV), and(S)-6-chloro-3-phenyl-indan-1-one, Compound (XVIII).

(S)-6-chloro-3-phenyl(d₅)-indan-1-one, Compound (XV), has proven to be avaluable building block in the synthesis of deuterated variants ofCompound (X) where the free phenyl group is deuterated.

General Experimental

Unless otherwise stated, all reactions were carried out under nitrogen.Reactions were monitored by thin-layer chromatography (TLC) analysis andLC-MS. All reagents were purchased and used without furtherpurification. Spots were visualized by exposure to ultraviolet (UV)light (254 nm), or by staining with a 5% solution of phosphomolybdenicacid (PMA) in ethanol or basic aqueous potassium permanganate (KMnO₄)and then heating. Column chromatography was carried out using Merck C60(40-63 μm, 230-240 mesh) silica gel. NMR spectra were recorded at 500 or600 MHz (′H NMR), and calibrated to the residual solvent peak. Thefollowing abbreviations are used for NMR data: s, singlet; d, doublet;t, triplet; m, multiplet. Coupling constants are rounded to nearest 0.5Hz. Enantiomeric excess was determined by chiral HPLC.

LC-MS Method

Acquity UPLC BEH C18 1.7 μm column; 2.1×50 mm operating at 60° C. withflow 1.2 mL/min of a binary gradient consisting of water+0.1% formicacid (A) and acetonitrile+5% water+0.1% formic acid (B).

Chiral HPLC Method

Phenomenex Lux 5μ Cellulose-2 column; 250×4.6 mm operating at 30° C.with flow 0.6 mL/min of n-hexane:isopropanol:diethylamine, 90:10:0.1.

Synthesis of (S)-6-chloro-3-phenyl(d₅)-indan-1-one (Compound (XV))(Scheme 14)

1-phenyl(d₅)-vinyl trifluoromethanesulfonate

To a solution of acetophenone-d₅ (1.56 g, 12.5 mmol) in CH₂Cl₂ (25.0 mL)was added trifluoromethanesulfonic anhydride (2.52 mL, 15.0 mmol) atroom temperature. Then, N,N-diisopropylethylamine (3.04 mL, 17.5 mmol)was added dropwise while the reaction mixture was cooled in an ice-waterbath. The reaction mixture was allowed to warm to room temperature, andit was stirred for 1.5 hours. Trifluoromethanesulfonic anhydride (0.63mL, 3.74 mmol) was added followed by N,N-diisopropylethylamine (1.09 mL,6.24 mmol). The reaction mixture was stirred for 2 hours at roomtemperature. Toluene (25 mL) and silica gel (5 g) were added. Themixture was concentrated in vacuo, and the resulting suspension wasfiltered through a pad of celite. The filter cake was washed withtoluene (10 mL), and the filtrate was evaporated to dryness in vacuo toyield crude Compound (XII) (3.11 g, 82%, purity (NMR): approx. 85%) as adark oil, that was used without further purification.

¹H NMR (600 MHz, CDCl₃) δ_(H) 5.38 (d, 1H, J=4.0 Hz), 5.62 (d, 1H, J=4.0Hz).

5-chloro-2-(1-phenyl(d₅)-vinyl)benzaldehyde (XIV) (Takagi, J.;Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124,8001-8006; Simeone, J. P.; Sowa, J. R. Jr., Tetrahedron 2007, 63,12646-12654; each herein incorporated by reference in its entirety).

To a solution of Compound (XII) (3.11 g, 10.3 mmol, purity (NMR):approximately 85%) in toluene was added triphenylphosphine (108 mg,0.685 mmol), bis(pinacolato)diboron (2.61 g, 10.3 mmol),bis(triphenylphosphine)palladium(II) chloride (240 mg, 0.342 mmol), andpotassium phenolate (1.92 g, 14.6 mmol). The reaction mixture wasstirred at 50° C. for 4 hours. This yielded Compound (XIII) in themixture, which was not isolated. The mixture was cooled to roomtemperature, and ethanol (10 mL) and water (5 mL) was added, followed bytetrakis(triphenylphosphine)palladium(0) (495 mg, 0.428 mmol), potassiumcarbonate (4.73 g, 34.2 mmol), and 2-bromo-5-chlorobenzaldehyde (1.88 g,8.56 mmol). The reaction mixture was stirred at 80° C. for 16 hours. Themixture was cooled to room temperature, and partitioned between water(50 mL) and toluene (50 mL).

The organic phase was separated and washed with water (50 mL) twice, andbrine. The organic phase was dried over MgSO₄, filtered, and evaporatedto dryness in vacuo. The residue was subjected to purification by columnchromatography eluting with 80:1 n-heptane:EtOAc mixture to affordCompound (XIV) (1.66 g, 74%) as an orange oil.

¹H NMR (600 MHz, CDCl₃) δ_(H) 5.28 (d, 1H, J=0.5 Hz), 6.00 (d, 1H, J=0.5Hz), 7.30 (d, 1H, J=8.0 Hz), 7.56 (dd, 1H; J=2.5, 8.0 Hz), 7.96 (d, 1H,J=2.5 Hz); ¹³C NMR (150 MHz, CDCl₃) δ_(C) 118.7, 126.6 (t, J=24.0 Hz),127.5, 128.2 (t, J=24.0 Hz), 128.4 (t, J=24.0 Hz), 132.5, 133.7, 134.7,135.7, 140.3, 143.9, 144.8, 190.8; LC-MS (APPI): m/e calc. forC₁₅H₇D₅ClO [M+H]⁺ 248.1, found 248.1.

(S)-6-Chloro-3-phenyl(d₅)-indan-1-one (XV) (Kundu, K.; McCullagh, J. V.;Morehead, A. T. Jr., J Am. Chem. Soc. 2005, 127, 16042-16043; hereinincorporated by reference in its entirety).

Hydrogen was bubbled through a N₂-flushed solution of((R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)(norbornadiene)rhodium(I)tetrafluoroborate (37 mg, 0.0404 mmol) in acetone (7.5 mL) for 10minutes at room temperature, during which the color of the solutionchanged from orange to more brownish red. The flask containing thesolution was subsequently flushed briefly with N₂ gas. Then, a solutionof (XIV) (526 mg, 2.02 mmol, purity (LC-MS): 95%) in acetone (7.5 mL)was added at room temperature. The reaction mixture was stirred for 24hours at room temperature. The reaction mixture was mixed with silicagel and evaporated to dryness in vacuo. The obtained material was loadedonto a silica gel column and the product was eluted with 10:1n-heptane:EtOAc mixture to obtain Compound (XV) (495 mg, 96%, 96.0% ee)as a solid.

¹H NMR (500 MHz, CDCl₃) δ_(H) 2.72 (dd, 1H, J=4.0, 19.5 Hz), 3.27 (dd,1H, J=8.0, 19.5 Hz), 4.55 (dd, 1H, J=4.0, 8.0 Hz), 7.21 (d, 1H; J=8.0Hz), 7.52 (dd, 1H, J=2.0, 8.0 Hz), 7.77 (d, 1H, J=2.0 Hz); ¹³C NMR (125MHz, CDCl₃) δ_(C) 44.0, 47.2, 123.2, 126.8 (t, J=24.0 Hz), 127.3 (t,J=24.0 Hz), 128.7 (t, J=24.0 Hz), 134.4, 135.1, 138.2, 142.9, 156.0,206.4; LC-MS (APPI): m/e calc. for C₁₅H₇D₅ClO [M+H]⁺ 248.1, found 247.6.

Synthesis of (S)-6-chloro-3-phenyl-indan-1-one (XVIII) (Scheme 15)

(E)-1-(5-chloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (XVI)

To an ice-cooled solution of sodium hydroxide (2.34 g, 58.6 mmol) inwater (17.0 mL) was added benzaldehyde (0.746 g, 7.03 mmol) and then asolution of 5-chloro-2-hydroxyacetophenone (1.00 g, 5.86 mmol) inmethanol (17.0 mL). The reaction mixture was allowed to warm to roomtemperature, and it was stirred for 24 hours. The bulk of the organicsolvent was removed by evaporation in vacuo. The aqueous residue wasextracted with EtOAc (3×30 mL). The combined extracts were washed withwater (50 mL) and brine (50 mL), dried over MgSO₄, filtered, andevaporated to dryness in vacuo. The residue was dissolved in a minimumvolume of CH₂Cl₂, and n-pentane was added which resulted inprecipitation. The obtained suspension was filtered and the precipitatewas washed with little cold pentane, and dried in vacuo to affordCompound (XVI) (695 mg, 46%) as an orange solid.

¹H NMR (500 MHz, CDCl₃) δ_(H) 6.22 (d, 1H, J=9.0 Hz), 6.80 (dd, 1H,J=3.0, 9.0 Hz), 7.33 (t, 1H, J=7.5 Hz), 7.38-7.42 (m, 4H), 7.60 (d, 2H,J=7.5 Hz); 8.63 (d, 1H, J=16.0 Hz); ¹³C NMR (125 MHz, CDCl₃) δ_(C)110.6, 125.2, 127.8, 128.1, 128.8, 128.9, 129.4, 129.6, 1′33.0, 136.4,137.1, 174.5, 188.2. Trifluoromethanesulfonic acid4-chloro-2-((E)-(3-phenyl-acryloyl))-phenyl ester (XVII):

To a solution of Compound (XVI) (517 mg, 2.00 mmol) in CH₂Cl₂ (10.0 mL)was added N,N-diisopropylethylamine (697 μL, 4.00 mmol).Trifluoromethanesulfonic anhydride (437 μL, 2.60 mmol) was addeddropwise at 0° C. The reaction mixture was stirred for 45 minutes at 0°C. Sat. aqueous NH₄Cl (5 mL) and water (10 mL) were added, and themixture was stirred for 5 minutes. The organic phase was separated andthe aqueous phase was extracted with CH₂Cl₂ (10 mL). The combinedextracts were dried over MgSO₄, filtered, and evaporated to dryness invacuo. The residue was purified by column chromatography eluting with4:1 n-heptane:EtOAc to yield (XVII) (757 mg, 97%) as an oil.

¹H NMR (500 MHz, CDCl₃) δ_(C) 7.16 (d, 1H, J=16.0 Hz), 7.34 (d, 1H,J=9.0 Hz), 7.40-7.47 (m, 3H), 7.57 (dd, 1H, J=2.5, 9.0 Hz), 7.60-7.62(m, 2H), 7.69 (d, 1H, 16.0 Hz), 7.72 (d, 1H, J=2.5 Hz); ¹³C NMR (125MHz, CDCl₃) δ_(C) 124.1, 124.2, 129.0, 129.2, 130.7, 131.5, 132.8,134.1, 134.6, 145.2, 147.8, 188.4.

(S)-6-Chloro-3-phenyl-indan-1-one (XVIII) (Minatti, A.; Zheng, X.;Buchwald, S. L., J. Org. Chem. 2007, 72, 9253-9258; herein incorporatedby reference in its entirety):

To a solution of Compound (XVII) (195 mg, 0.500 mmol) in DMF (2.0 mL)was added proton-sponge (214 mg, 1.00 mmol), palladium acetate (6 mg,0.025 mmol), and (R)-3,5-XylMeOBIPHEP (35 mg, 0.05 mmol) at roomtemperature. The reaction mixture was stirred at 85° C. for 45 hours.The mixture was cooled to room temperature and diluted with TBME (15mL). The mixture was washed three times with water (3×20 mL), and theorganic phase was dried over MgSO₄, filtered, and evaporated to drynessin vacuo. The residue was subjected to column chromatography elutingwith 10:1 n-heptane:EtOAc to yield Compound (XVII) (94 mg, 77%, 64.0%ee).

¹H NMR (600 MHz, CDCl₃) δ_(H) 2.71 (dd, 1H, J=4.0, 19.5 Hz), 3.25 (dd,1H, J=8.0, 19.5 Hz), 4.54 (dd, 1H, J=4.0, 8.0 Hz), 7.10 (d, 2H, J=7.0Hz), 7.20 (d, 1H, J=8.0 Hz), 7.25 (t, 1H, J=7.5 Hz), 7.31 (t, 2H, J=7.5Hz), 7.50 (dd, 1H, J=2.0, 8.0 Hz), 7.75 (d, 2H, J=2.0 Hz); ¹³C NMR (150MHz, CDCl₃) δ_(C) 44.1, 47.2, 123.3, 127.3, 127.6, 128.3, 129.1, 134.4,135.2, 138.3, 143.1, 156.1, 204.5.

Enantioenrichment of Compound (XVIII) by Reprecipitation:

Compound (XVII) (940 mg, 3.87 mmol, 96% ee) was dissolved in a minimumvolume of boiling ethanol (99% v/v). The resulting solution was allowedto cool slowly to room temperature by placing the glass flask containingthe solution in the air. A precipitate formed that was filtered fromsolution to yield Compound (XVIII) (700 mg, 99.9% ee, 74%). A secondbatch of Compound (XVIII) could be obtained by cooling the filtrate inthe freezer (−8° C.) to yield Compound (XVIII) (80 mg, 98.6% ee, 9%).

Analytical data (NMR and LC-MS) for Compound (XVIII) were the same asthose reported above.

Example 14: Large Scale Production of Compound (IV)

The following process was developed for the large-scale production ofthe hydrogen tartrate salt of Compound (IV).

General Procedure:

-   -   1.) 2.01 kg (16.9 mol) thionylchloride and 7.2 kg        tetrahydrofuran are mixed and the reaction is cooled to 10-15°        C.;    -   2.) a solution of 2.76 kg (11.1 mol) (XXII) in 7.2 kg THF is        slowly added and after completion 5.9 kg tetrahydrofuran is        added;    -   3.) the reaction is stirred at 15° C. for approximately 90        hours;    -   4.) 16.7 kg water is cooled to 11° C. and added slowly to the        reaction, afterwards 7.8 kg 27.7% aqueous sodium hydroxide is        added slowly, followed by 10 kg ethylacetate;    -   5.) the mixture is stirred for 20-40 minutes;    -   6.) the phases are separated and the organic phase is reduced to        a volume of approximately 6 L;    -   7.) 16 kg methyl isobutylketone is added and the volume is        reduced to approximately 8 L;    -   8.) 1.58 kg (11.4 mol) potassium carbonate, 1.69 kg (14.8 mol)        2,2-dimethylpiperazin, and 13.6 kg methyl isobutyl ketone are        added;    -   9.) the reaction is stirred 35 hours at 90-95° C.;    -   10.) after cooling to room temperature, 11 kg water is added and        the mixture is stirred for 30-60 minutes;    -   11.) the phases are separated, 13.7 kg water is added to the        organic phase, and the mixture is stirred slowly for 30-60        minutes;    -   12.) the phases are separated and the organic phase is blank        filtered;    -   13.) 5 kg methyl isobutyl ketone, 7.8 kg water, and 5.9 kg 36%        aqueous hydrogen chloride are added and the mixture is stirred        at 50° C. for 30-60 minutes;    -   14.) the phases are separated, 8 kg methyl isobutyl ketone is        added to the water phase, and the mixture is cooled to 10-15°        C.;    -   15.) a mixture of 3.5 kg methyl isobutyl ketone and 7.8 kg 25%        aqueous ammonia are slowly added to the mixture and the reaction        is stirred at 20-25° C. for 60-90 minutes;    -   16.) the phases are separated and the organic phase is washed        with 10.5 kg water;    -   17.) the organic phase is reduced to 8 L;    -   18.) 1.19 kg (10.25 mol) maleic acid and 9 kg methyl isobutyl        ketone are added and the reaction is afterwards warmed to 75-80°        C.;    -   19.) after cooling to 10-15° C., the precipitate is filtered off        and washed with 10 kg methyl isobutyl ketone; and    -   20.) the solid is dried in a vacuum oven at 50° C. for        approximately 20 hours to give 3.47 kg (68% yield) of (XXV)        maleate.        NMR Data for (XXV) Maleate

¹H-NMR (DMSO-d₆, 600 MHz, ppm): 8.60 (bs, 2H, maleic acid), 7.39 (d, 1H,J=1.6 Hz), 7.29 (dd, 1H, J=8.0 Hz, J=1.8 Hz), 6.98 (d, 1H, J=8.2 Hz),6.04 (s, 2H, maleic acid), 4.56 (dd, 1H, J=8.1 Hz, J=4.9 Hz), 4.48 (dd,1H, J=8.6 Hz, J=6.2 Hz), 3.37 (bs, 1H), 3.16 (bs, 2H), 2.77 (bs, 1H),2.58-2.50 (m, 3H), 2.31 (d, 1H, J=12.0 Hz), 2.12 (ddd, 1H, J=13.8 Hz,J=8.0 Hz, J=6.0 Hz), 1.33 (s, 3H), 1.31 (s, 3H).

Procedure:

-   -   1.) 1.1 kg (2.38 mol) (XXV) maleate, 11 L methyl tertbutyl        ether, 1.8 L water, and 1 L 25% aqueous ammonia are stirred for        1-2 hours;    -   2.) the phases are separated and the organic phase is washed        twice with 2 L water;    -   3.) a solution of 254 g (3.85 mol) 85% aqueous potassium        hydroxide and 1.5 L water is added to the organic phase,        followed by addition of 450 g (3.11 mol) methyl(d₃)iodide        (CD₃I);    -   4.) the reaction is stirred at 20-25° C. for 16-24 hours;    -   5.) 2 L water are added and the precipitating by-product is        filtered off;    -   6.) 0.8 L water and 0.2 L 25% aqueous ammonia are added to the        filtrate and the mixture is stirred for 20-40 minutes;    -   7.) the phases are separated and the organic phase is washed        with 2 L water;    -   8.) the phases are separated and 38 g (0.48 mol) acetylchloride        is added to the organic phase which is stirred for 20-40        minutes;    -   9.) 0.8 L water and 0.2 L 25% aqueous ammonia are added and the        mixture is stirred for 20-40 minutes;    -   10.) the phases are separated and the organic phase is washed        with 2 L water;    -   11.) the organic phase is reduced to dryness and acetone is        added;    -   12.) 225 g (1.91 mol) succinic acid and acetone are added so        that the reaction volume is approximately 6-6.5 L;    -   13.) the reaction is warmed to reflux and afterwards cooled to        5-10° C.;    -   14.) the precipitate is filtered off and washed with 1 L        acetone; and    -   15.) the solid is dried in a vacuum oven at 50° C. for more than        16 hours to give 630 g (55% yield) of (XXVII) succinate.        NMR Data for (XXVII) Succinate

¹H-NMR (DMSO-d₆, 600 MHz, ppm): 7.33 (d, 1H, J=1.9 Hz), 7.26 (dd, 1H,J=8.1 Hz, J=2.0 Hz), 6.95 (d, 1H, J=8.0 Hz), 4.46 (dd, 1H, J=8.0 Hz,J=5.1 Hz), 4.46 (dd, 1H, J=8.8 Hz, J=5.8 Hz), 2.65-2.56 (m, 4H),2.46-2.41 (m, 1H), 2.37 (s, 4H, succinic acid), 2.31 (bs, 1H), 2.13 (d,1H, J=10.9 Hz), 2.02 (ddd, 1H, J=13.7 Hz, J=7.8 Hz, J=6.0 Hz), 1.04 (s,3H), 1.02 (s, 3H).

Procedure:

-   -   1.) 1.0 kg (2.08 mol) (XXVII) succinate, 8 L ethyl acetate, 2 L        water, and 1 L 25% aqueous ammonia are stirred for 0.5-1 hours;    -   2.) the phases are separated and the organic phase is washed        with 2 L water;    -   3.) the organic phase is reduced to approximately 1.5 L;    -   4.) 10 L acetone and 312 g (2.08 mol) L(+)-tartaric acid are        added;    -   5.) the reaction is warmed to reflux and afterwards cooled to        5-10° C.;    -   6.) the precipitate is filtered off, washed with 1.2 L acetone;    -   7.) the wet filtercake is recharged and 11 L absolute ethanol        are added;    -   8.) the reaction is warmed to reflux and afterwards cooled to        5-10° C.;    -   9.) the precipitate is filtered off and washed with 1.2 L        absolute ethanol; and    -   10.) the solid is dried in a vacuum oven at 50° C. for more than        16 hours to give 395 g (37% yield) of (IV) L(+)-hydrogen        tartrate.        NMR Data for (IV) L(+)-Hydrogen Tartrate

¹H-NMR (DMSO-d₆, 600 MHz, ppm): 7.36 (s, 1H), 7.27 (d, 1H, J=8.2 Hz),6.96 (d, 1H, J=8.2 Hz), 4.50 (dd, 1H, J=8.0 Hz, J=5.1 Hz), 4.45 (dd, 1H,J=8.5 Hz, J=5.8 Hz), 4.07 (s, 2H, tartrate), 2.95 (bs, 1H), 2.77 (bs,1H), 2.61-2.50 (m, 3H), 2.31 (d, 1H, J=11.7 Hz), 2.04 (ddd, 1H, J=13.7Hz, J=7.8 Hz, J=6.0 Hz) 1.21 (s, 3H), 1.18 (s, 3H).

Example 15: Physico-Chemical Characterization of Salts of Compound (IV)

pK_(a) and Log P/D of Compound (IV)

pK_(a) was determined by potentiometric titration of the base at ionstrength 0.16 using MeOH as co-solvent. Three series of three repeatedtitrations on the same solution of the sample was performed in aconventional way from low to high pH and a difference curve was createdfrom each of these titrations by blank subtraction. The apparentpK_(a)-value at each MeOH:water ratio is calculated from the differencecurves, and the pK_(a) value is determined by extrapolation to zero MeOHcontent.

The lower pK_(a) value is too low to be determined by potentiometrictitration as data only were found reliable down to −3. The high pK_(a)was determined to be 8.9±0.1.

The lower pK_(a) was determined by Dip Probe Absorption Spectroscopydetection during titration of the base at ion strength 0.16 using MeOHas co-solvent. The change in absorption spectra as a function ofionisation is used to calculate the pK_(a) value. Two series of threerepeated titrations on the same solution of the sample was performedfrom low to high pH, with a photo diode array as additional detection.The apparent pK_(a) value at each MeOH:water ratio is calculated bytarget factor analysis on the change in absorption spectra, and thepK_(a) value is determined by extrapolation to zero MeOH content.

Result: The lower pK_(a) was determined to be 2.5±0.1.

The log D profile was determined by titration at 27° C. and ion strengthof approximately 0.16. A series of three repeated titrations on the samesample in solution was performed, from low to high pH. The firsttitration was performed with a small amount of n-octanol present in thesolution, the second and third with increasing amounts.

A difference curve was created from each of these titrations by blanksubtraction, and from these difference curves, the apparent pK_(a)values (p_(o)K_(a)) were calculated. From the change in the apparentpK_(a) values (ΔpK_(a)) with the n-octanol:water ratio combined with thereal pK_(a) value, the Log P value was calculated and the Log D profilewas derived. The following values were determined: Log P=5.4±0.4 and LogD_(7.4)=3.9±0.4.

Melting Point Determined by DSC

The melting point of the (R,R)-hydrogen tartrate salt of Compound (IV)was determined using differential scanning calorimetry (DSC), using a TAinstruments DSC Q1000 heating the sample 5°/minute. The sample wasplaced in a covered pan with a punched pinhole.

The melting is characterized by onset and peak temperature of themelting endotherm, and the enthalpy of fusion is calculated from thearea of the peak. Based on the DSC thermogram an onset temperature of187.4° C. and a peak maximum at 189.4° C. was found. The enthalpy offusion was 96 J/g corresponding to 49 kJ/mol, however the thermogram isindicative that the melting happens under decomposition meaning that theenthalpy probably contain energy other than melting.

Solubility

Solubility of the (R,R)-hydrogen tartrate salt of Compound (IV) wasmeasured in aqueous solutions and in cyclodextrins with the followingresults (Table 5):

TABLE 5 Solubility of (R,R)-hydrogen tartrate salt of Compound (IV).Solvent Meas. conc. (mg base/ml) pH Hydrogen tartrate in water, 5° C.3.1 3.25 Hydrogen tartrate in water, room 4.0 3.15 temperature Hydrogentartrate in water, 37° C. 6.6 3.08 10% HPβCD 25.2 3.59  5% HPβCD, at RT15.5 3.61  5% HPβCD, at 5° C. 12Polymorphism

One solvent free crystal form of the hydrogen tartrate has beenisolated. The XRPD of this form is shown in FIG. 18, and designatedherein as “polymorph A”.

Salts of Compound (IV)

Four salts were prepared by precipitation of Compound (IV) from 99%EtOH. Analytical data are given in the table below (Table 6).

TABLE 6 Data for salts of Compound (IV) Salt DSC (T_(onset)° C.)Solubility (mg/ml) pH Dihydrogen phosphate Degradation at 1.4 4.67 250°C. Hydrogen fumarate 202.7° C. 1.2 4.10 Hydrogen maleate 150.4° C. 1.24.94 Hydrogen malonate 145.0° C. followed 9.5 4.08 by degradationHydrogen tartrate   187° C. 4.0 3.15 Base 59.9 0.1 7.6

Although the invention has been described and illustrated in theforegoing illustrative embodiments, it is understood that the presentdisclosure has been made only by way of example, and that numerouschanges in the details of implementation of the invention can be madewithout departing from the spirit and scope of the invention, which islimited only by the claims that follow. Features of the disclosedembodiments can be combined and/or rearranged in various ways within thescope and spirit of the invention to produce further embodiments thatare also within the scope of the invention. Those skilled in the artwill recognize, or be able to ascertain, using no more than routineexperimentation, numerous equivalents to the specific embodimentsdescribed specifically in this disclosure. Such equivalents are intendedto be encompassed in the scope of the following claims.

The invention claimed is:
 1. A method of treating schizophrenia,schizophreniform disorder, or schizoaffective disorder in a subject inneed thereof comprising administration of an effective amount of ahydrogen fumarate salt of a deuterium enriched compound of formula Y:

wherein, R¹-R¹⁰ are independently hydrogen or deuterium, wherein atleast two of R¹-R¹⁰ are deuterium.
 2. The method of claim 1, furthercomprising administration of at least one neuroleptic agent.
 3. Themethod of claim 2, wherein the neuroleptic agent is selected from thegroup consisting of sertindole, olanzapine, risperidone, quetiapine,aripiprazole, haloperidol, clozapine, ziprasidone, and osanetant.
 4. Themethod of claim 1, wherein the compound is


5. The method of claim 1, wherein the compound is


6. The method of claim 1, wherein the compound is


7. The method of claim 1, wherein the compound is


8. The method of claim 1, wherein the compound is


9. The method of claim 1, wherein the compound is